The role of the thalamus in modular functional networks in temporal lobe epilepsy with cognitive impairment.

OBJECTIVE: Cognitive deficit is common in patients with temporal lobe epilepsy (TLE). Here, we aimed to investigate the modular architecture of functional networks associated with distinct cognitive states in TLE patients together with the role of the thalamus in modular networks. METHODS: Resting-state functional magnetic resonance imaging scans were acquired from 53 TLE patients and 37 matched healthy controls. All patients received the Montreal Cognitive Assessment test and accordingly were divided into TLE patients with normal cognition (TLE-CN, n = 35) and TLE patients with cognitive impairment (TLE-CI, n = 18) groups. The modular properties of functional networks were calculated and compared including global modularity Q, modular segregation index, intramodular connections, and intermodular connections. Thalamic subdivisions corresponding to the modular networks were generated by applying a 'winner-take-all' strategy before analyzing the modular properties (participation coefficient and within-module degree z-score) of each thalamic subdivision to assess the contribution of the thalamus to modular functional networks. Relationships between network properties and cognitive performance were then further explored. RESULTS: Both TLE-CN and TLE-CI patients showed lower global modularity, as well as lower modular segregation index values for the ventral attention network and the default mode network. However, different patterns of intramodular and intermodular connections existed for different cognitive states. In addition, both TLE-CN and TLE-CI patients exhibited anomalous modular properties of functional thalamic subdivisions, with TLE-CI patients presenting a broader range of abnormalities. Cognitive performance in TLE-CI patients was not related to the modular properties of functional network but rather to the modular properties of functional thalamic subdivisions. CONCLUSIONS: The thalamus plays a prominent role in modular networks and potentially represents a key neural mechanism underlying cognitive impairment in TLE.

Morphological and metabolic asymmetries of the thalamic subregions in temporal lobe epilepsy predict cognitive functions.

Both morphological and metabolic imaging were used to determine how asymmetrical changes of thalamic subregions are involved in cognition in temporal lobe epilepsy (TLE). We retrospectively recruited 24 left-TLE and 15 right-TLE patients. Six thalamic subnuclei were segmented by magnetic resonance imaging, and then co-registered onto Positron emission tomography images. We calculated the asymmetrical indexes of the volumes and normalized standard uptake value ratio (SUVR) of the entire and individual thalamic subnuclei. The SUVR of ipsilateral subnuclei were extensively and prominently decreased compared with the volume loss. The posterior and medial subnuclei had persistently lower SUVR in both TLE cases. Processing speed is the cognitive function most related to the metabolic asymmetry. It negatively correlated with the metabolic asymmetrical indexes of subregions in left-TLE, while positively correlated with the subnuclei volume asymmetrical indexes in right-TLE. Epilepsy duration negatively correlated with the volume asymmetry of most thalamic subregions in left-TLE and the SUVR asymmetry of ventral and intralaminar subnuclei in right-TLE. Preserved metabolic activity of contralateral thalamic subregions is the key to maintain the processing speed in both TLEs. R-TLE had relatively preserved volume of the ipsilateral thalamic volume, while L-TLE had relatively decline of volume and metabolism in posterior subnucleus.

Intracranial Neurofeedback Modulating Neural Activity in the Mesial Temporal Lobe During Memory Encoding: A Pilot Study.

Removal of the mesial temporal lobe (MTL) is an established surgical procedure that leads to seizure freedom in patients with intractable MTL epilepsy; however, it carries the potential risk of memory damage. Neurofeedback (NF), which regulates brain function by converting brain activity into perceptible information and providing feedback, has attracted considerable attention in recent years for its potential as a novel complementary treatment for many neurological disorders. However, no research has attempted to artificially reorganize memory functions by applying NF before resective surgery to preserve memory functions. Thus, this study aimed (1) to construct a memory NF system that used intracranial electrodes to feedback neural activity on the language-dominant side of the MTL during memory encoding and (2) to verify whether neural activity and memory function in the MTL change with NF training. Two intractable epilepsy patients with implanted intracranial electrodes underwent at least five sessions of memory NF training to increase the theta power in the MTL. There was an increase in theta power and a decrease in fast beta and gamma powers in one of the patients in the late stage of memory NF sessions. NF signals were not correlated with memory function. Despite its limitations as a pilot study, to our best knowledge, this study is the first to report that intracranial NF may modulate neural activity in the MTL, which is involved in memory encoding. The findings provide important insights into the future development of NF systems for the artificial reorganization of memory functions.

Seizure and anatomical outcomes of repeat laser amygdalohippocampotomy for temporal lobe epilepsy: A single-institution case series.

OBJECTIVE: In patients with treatment-refractory temporal lobe epilepsy (TLE), a single stereotactic laser interstitial thermotherapy (LITT) procedure is sometimes insufficient to ablate epileptogenic tissue, particularly the medial structures often implicated in TLE. In patients with seizure recurrence after initial ablation, the extent to which a second ablation may achieve improved seizure outcomes is uncertain. The objective of this study was to investigate the feasibility and potential efficacy of repeat LITT amygdalohippocampotomy as a worthwhile strategy for intractable temporal lobe epilepsy by quantifying changes to targeted mesial temporal lobe structures and seizure outcomes. METHODS: Patients who underwent two LITT procedures for drug-resistant mesial TLE at our institution were included in the study. Lesion volumes for both procedures were calculated by comparing post-ablation intraoperative sequences to preoperative anatomy. Clinical outcomes after the initial procedure and repeat procedure were classified according to Engel scores. RESULTS: Five consecutive patients were included in this retrospective case series: 3 with right- and 2 with left-sided TLE. The median interval between LITT procedures was 294 days (range: 227-1918). After the first LITT, 3 patients experienced class III outcomes, 1 experienced a class IV, and 1 experienced a class IB outcome. All patients achieved increased seizure freedom after a second procedure, with class I outcomes (3 IA, 2 IB). CONCLUSIONS: Repeat LITT may be sufficient to achieve satisfactory seizure outcomes in some individuals who might otherwise be considered for more aggressive resection or palliative neuromodulation. A larger study to establish the potential value of repeat LITT amygdalohippocampotomy vs. other re-operation strategies for persistent, intractable temporal lobe epilepsy is worth pursuing.

Multi-scale structural alterations of the thalamus and basal ganglia in focal epilepsy using 7T MRI.

Focal epilepsy is characterized by repeated spontaneous seizures that originate from cortical epileptogenic zone networks (EZN). Analysis of intracerebral recordings showed that subcortical structures, and in particular the thalamus, play an important role in seizure dynamics as well, supporting their structural alterations reported in the neuroimaging literature. Nonetheless, between-patient differences in EZN localization (e.g., temporal vs. non-temporal lobe epilepsy) as well as extension (i.e., number of epileptogenic regions) might impact the magnitude as well as spatial distribution of subcortical structural changes. Here we used 7 Tesla MRI T1 data to provide an unprecedented description of subcortical morphological (volume, tissue deformation, and shape) and longitudinal relaxation (T1 ) changes in focal epilepsy patients and evaluate the impact of the EZN and other patient-specific clinical features. Our results showed variable levels of atrophy across thalamic nuclei that appeared most prominent in the temporal lobe epilepsy group and the side ipsilateral to the EZN, while shortening of T1 was especially observed for the lateral thalamus. Multivariate analyses across thalamic nuclei and basal ganglia showed that volume acted as the dominant discriminator between patients and controls, while (posterolateral) thalamic T1 measures looked promising to further differentiate patients based on EZN localization. In particular, the observed differences in T1 changes between thalamic nuclei indicated differential involvement based on EZN localization. Finally, EZN extension was found to best explain the observed variability between patients. To conclude, this work revealed multi-scale subcortical alterations in focal epilepsy as well as their dependence on several clinical characteristics.

Reprogramming the Circadian Dynamics of Epileptic Genes in Mouse Temporal Lobe Epilepsy.

Temporal lobe epilepsy (TLE) is a common and severe epilepsy displaying rhythmicity in humans and animals. However, how the circadian clock contributes to TLE remains elusive. A recent circadian analysis of the ventral hippocampal transcriptome of pilocarpine-induced TLE mice revealed as many as 1650 rhythmically expressed transcripts. Here, a comparison of the mouse ventral hippocampal transcriptome with the human epilepsy-related gene set identified 315 possible mouse epilepsy-related genes. Rhythmicity analysis classified them into arrhythmicity, loss-of-rhythmicity, gain-of-rhythmicity, and rhythmicity-maintaining groups. KEGG and GO analyses of these mouse epilepsy genes suggest their involvement in circadian entrainment. In TLE mice, Htr1d, Drd2, and Chrna3 lose rhythmicity, but P2rx7 gains rhythmicity; the up-regulation of Htr1d and Drd2 and down-regulation of Chrna3 inhibit adenylate cyclase (AC), and up-regulation of Htr1d, Drd2, and P2rx7 activates protein kinase C (PKC). Together, these results suggest that epilepsy can disrupt the circadian dynamics of the epileptic genes, shed light on possible TLE pathogenesis, and provide potential targets for TLE diagnosis and chronotherapy.

The Thalamic and Intracortical Inhibitory Function of Somatosensory System Is Unchanged in Mesial Temporal Lobe Epilepsy With Hippocampal Sclerosis.

PURPOSE: In mesial temporal lobe epilepsy with hippocampal sclerosis, there is parietal atrophy and cognitive involvement in related domains. In this context, we hypothesized that inhibitory input into somatosensory cortex and thalamus may be increased in these patients, which could improve after epilepsy surgery. Thus, we analyzed the inhibitory function of somatosensory system by studying surround inhibition (SI) and recovery function of somatosensory evoked potentials in patients with mesial temporal lobe epilepsy with hippocampal sclerosis. METHODS: Nine patients with unoperated mesial temporal lobe epilepsy with hippocampal sclerosis, 10 patients who underwent epilepsy surgery, and 12 healthy subjects were included. For SI of somatosensory evoked potentials, we recorded somatosensory evoked potentials after stimulating median or ulnar nerve at wrist separately and after median and ulnar nerves simultaneously and calculated SI% in all participants. For recovery function of somatosensory evoked potentials, paired stimulation of median nerve at 40- and 100-millisecond intervals was performed. We compared the findings among groups. As a secondary analysis, we determined the outliers in the patient group and analyzed the relation to the clinical findings. RESULTS: The mean SI% or recovery function was similar among three groups. However, there were five patients with SI loss on normal side in the patient group, which was related to the antiseizure drugs. CONCLUSIONS: In contrast to our hypothesis, both intracortical (SI) and thalamic/striatal (recovery function) inhibitory modulation of the somatosensory cortex was not altered in mesial temporal lobe epilepsy with hippocampal sclerosis and did not differ in surgical and nonsurgical groups.

Amplitude synchronization of spontaneous activity of medial and lateral temporal gyri reveals altered thalamic connectivity in patients with temporal lobe epilepsy.

In this study, we examined whether amplitude synchronization of medial (MTL) and lateral (LTL) temporal lobes can detect unique alterations in patients with MTL epilepsy (mTLE) with mesial temporal sclerosis (MTS). This was a retrospective study of preoperative resting-state fMRI (rsfMRI) data from 31 patients with mTLE with MTS (age 23-69) and 16 controls (age 21-35). fMRI data were preprocessed based on a multistep preprocessing pipeline and registered to a standard space. Using each subject's T1-weighted scan, the MTL and LTL were automatically segmented, manually revised and then fit to a standard space using a symmetric normalization registration algorithm. Dual regression analysis was applied on preprocessed rsfMRI data to detect amplitude synchronization of medial and lateral temporal segments with the rest of the brain. We calculated the overlapped volume ratio of synchronized voxels within specific target regions including the thalamus (total and bilateral). A general linear model was used with Bonferroni correction for covariates of epilepsy duration and age of patient at scan to statistically compare synchronization in patients with mTLE with MTS and controls, as well as with respect to whether patients remained seizure-free (SF) or not (NSF) after receiving epilepsy surgery. We found increased ipsilateral positive connectivity between the LTLs and the thalamus and contralateral negative connectivity between the MTLs and the thalamus in patients with mTLE with MTS compared to controls. We also found increased asymmetry of functional connectivity between temporal lobe subregions and the thalamus in patients with mTLE with MTS, with increased positive connectivity between the LTL and the lesional-side thalamus as well as increased negative connectivity between the MTL and the nonlesional-side thalamus. This asymmetry was also seen in NSF patients but was not seen in SF patients and controls. Amplitude synchronization was an effective method to detect functional connectivity alterations in patients with mTLE with MTS. Patients with mTLE with MTS overall showed increased temporal-thalamic connectivity. There was increased functional involvement of the thalamus in MTS, underscoring its role in seizure spread. Increased functional thalamic asymmetry patterns in NSF patients may have a potential role in prognosticating patient response to surgery. Elucidating regions with altered functional connectivity to temporal regions can improve understanding of the involvement of different regions in the disease to potentially target for intervention or use for prognosis for surgery. Future studies are needed to examine the effectiveness of using patient-specific abnormalities in patterns to predict surgical outcome.

Electroacupuncture Promotes Autophagy by Regulating the AKT/mTOR Signaling Pathway in Temporal Lobe Epilepsy.

Temporal lobe epilepsy (TLE) is a complex neurological disease, and its occurrence and development are closely related to the autophagy signaling pathway. However, the mechanism by which electroacupuncture (EA) affects the regulation of autophagy has not been fully elucidated. TLE gene chip dataset GSE27166 and data from rats without epilepsy (n = 6) and rats with epilepsy (n = 6) were downloaded from Gene Expression Omnibus. The differentially expressed genes (DEGs) in the TLE and control groups were identified with the online tool GEO2R. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases were used to analyse the functional and pathway enrichment of genes in the most important modules. A rat model of TLE induced by lithium-pilocarpine treatment was established. EA treatment at DU20 and DU14 in TLE rats was performed for 2 weeks. Neuronal regeneration was determined using immunofluorescence staining. The protein levels of AKT/mTOR signaling pathway and autophagy markers were detected through western blotting and immunohistochemistry. This study identified 1837 DEGs, including 798 upregulated genes and 1039 downregulated genes. GO enrichment and KEGG analyses were performed on DEGs and revealed functional enrichment mainly in the mTOR signaling pathway and autophagy-animal. Furthermore, the number of mature neurons was significantly increased upon coexpressing BrdU/NeuN in TLE rats treated with EA. Western blotting and immunohistochemistry results showed significantly decreased levels of the phosphorylated-AKT and p-mTOR in the hippocampal CA3 and DG regions of TLE rats with EA treatment. And increased p-ULK1/ULK1, LC3-II/LC3-I and p62 levels in TLE rats with EA stimulation. Therefore, this study suggested that EA promoted autophagy in hippocampal neurons during the onset of epilepsy by regulating the AKT/mTOR signaling pathway to treat epilepsy.

Neuropsychological features of mind wandering in left-, right- and extra temporal lobe epilepsy.

PURPOSE: Mind wandering, i.e. mental time-travelling and imagery unrelated to the current situation has recently been related to mesial temporal lobe (memory) function. In this regard we evaluated as to whether parameters of mind wandering are related to material specific memory in patients with a left-, right-, or extra- temporal lobe epilepsy. METHODS: In this prospective controlled study we analyzed mind wandering, material specific memory, and executive functions in 29 right-handed patients with right-, left-, or extra-temporal lobe epilepsies. Mind wandering was assessed with a sustained attention to response task containing embedded inquiries on mind wandering. In addition, verbal list learning and memory (VLMT), design list learning (DCS-R), and executive function (EpiTrack) were assessed. RESULTS: In patients with right temporal lobe epilepsy, the propensity to mind wander was positively related to verbal memory performance, while in left temporal lobe epilepsy, the propensity and future related mind wandering were positively correlated to the performance in visual/figural memory. Generally, the propensity of MW was related to executive function as well. CONCLUSION: The results suggest that mind wandering in lateralized temporal lobe epilepsy appears to be non-specifically driven by executive function and specifically by the mode and functionality of the memory system of the non-epileptic hemisphere. Repeated assessments would be required to discern as to how much such patterns depend on lesions versus epileptic dysfunction and whether they change with successful medical or surgical treatment.

Oral glutamine supplementation increases seizure severity in a rodent model of mesial temporal lobe epilepsy.

Background: Glutamine synthetase (GS) is the only enzyme known to synthesize significant amounts of glutamine in mammals, and loss of GS in the hippocampus has been implicated in the pathophysiology of medication refractory mesial temporal lobe epilepsy (MTLE). Moreover, loss-of-function mutations of the GS gene causes severe epileptic encephalopathy, and supplementation with glutamine has been shown to normalize EEG and possibly improve the outcome in these patients. Here we examined whether oral glutamine supplementation is an effective treatment for MTLE by assessing the frequency and severity of seizures after supplementation in a translationally relevant model of the disease.Methods: Male Sprague Dawley rats (380-400 g) were allowed to drink unlimited amounts of glutamine in water (3.6% w/v; n = 8) or pure water (n = 8) for several weeks. Ten days after the start of glutamine supplementation, GS was chronically inhibited in the hippocampus to induce MTLE. Continuous video-intracranial EEG was collected for 21 days to determine the frequency and severity of seizures.Results: While there was no change in seizure frequency between the groups, the proportion of convulsive seizures was significantly higher in glutamine treated animals during the first three days of GS inhibition.Conclusion: The results suggest that oral glutamine supplementation transiently increases seizure severity in the initial stages of an epilepsy model, indicating a potential role of the amino acid in seizure propagation and epileptogenesis.

Costs Associated with Laser Interstitial Thermal Therapy Are Lower Than Anterior Temporal Lobectomy for Treatment of Temporal Lobe Epilepsy.

BACKGROUND: Laser interstitial thermal therapy (LITT) is a minimally invasive alternative to anterior temporal lobectomy (ATL) for treatment of temporal lobe epilepsy. It has gained popularity as familiarity with technique increases and outcomes are better characterized. There has been no direct cost comparison between the 2 techniques in literature to date. The current study directly compares hospital costs associated with LITT with those of ATL patients and analyzes the factors potentially responsible for those costs. METHODS: Patients who underwent ATL (27) and LITT (15) were retrospectively reviewed for total hospital costs along with demographic, surgical, and postoperative factors potentially affecting cost. T-tests were used to compare costs and independent linear regressions, and hierarchical regressions were used to examine predictors of cost for each procedure. RESULTS: Mean hospital costs of admission for single-trajectory LITT ($104,929.88) were significantly less than for ATL ($134,980.04) (P = 0.001). In addition, length of stay, anesthesia costs, operative room costs, and postoperative hospitalization costs were all significantly lower in LITT. CONCLUSIONS: Given the minimally invasive nature of LITT, it is associated with shorter length of stay and lower hospital costs than ATL in the first head-to-head comparison of procedural costs in literature to date. Long-term efficacy as it relates to these costs associated with LITT and ATL should be further investigated to better characterize the utility of LITT in temporal lobe epilepsy patients.

Long-term music adjuvant therapy enhances the efficacy of sub-dose antiepileptic drugs in temporal lobe epilepsy.

AIMS: Noninvasive music adjuvant therapy shows great potential in improving seizure control when combined with routine antiepileptic drugs. However, the diversity of previous music protocols has resulted in disparate outcomes. The optimized protocol and features for music adjuvant therapy are still not fully understood which limits its feasibility. METHODS: By applying different regimens of music therapy in various temporal lobe epilepsy models, we evaluated the effect of music in combination with sub-dose drugs on epileptic seizures to determine the optimized protocol. RESULTS: A subgroup of kindled mice that were responsive to music adjuvant therapy was screened. In those mice, sub-dose drugs which were noneffective on kindled seizures, alleviated seizure severity after 12 h/day Mozart K.448 for 14 days. Shorter durations of music therapy (2 and 6 h/day) were ineffective. Furthermore, only full-length Mozart K.448, not its episodes or other music varieties, was capable of enhancing the efficacy of sub-dose drugs. This music therapeutic effect was not due to increasing cerebral drug concentration, but instead was related with the modulation of seizure electroencephalogram (EEG) spectral powers in the hippocampus. CONCLUSION: These results indicate that long-term full-length Mozart K.448 could enhance the anti-seizure efficacy of sub-dose drugs and may be a promising noninvasive adjuvant therapy for temporal lobe epilepsy.

Anticonvulsant effects of Cymbopogon giganteus extracts with possible effects on fully kindled seizures and anxiety in experimental rodent model of mesio-temporal epilepsy induced by pilocarpine.

ETHNOPHARMACOLOGICAL RELEVANCE: Epilepsy is a neurological disorder of the brain characterized by periodic and unpredictable occurrence of a transient behavior alteration due to the rhythmic, synchronous and disordered firing of brain neuron. Worldwide, approximately 50 million people currently live with epilepsy and close to 80% of people with epilepsy live in poor countries. However, it was noticed in many countries worldwide that people with epilepsy and their families suffer from stigma and discrimination and that situation exposes them to high psychological conditions such as depression and anxiety as well as more physical problems including bruising and fractures from injuries related to seizures. However, several plants-based products used for epilepsy and anxiety treatments in different system of folk medicine have exhibited a significant anti-epileptic and antianxiety activities using animal models with fewer side effects. AIM OF THE STUDY: The study aimed at evaluating the antiepileptic, status post-epilepticus and anxiolytic effects of Cymbopogon giganteus decoction in rat model induced by pilocarpine. MATERIALS AND METHODS: A total of 90 rats were partitioned into 7 groups and treated as follow: animals of groups I (normal control) and II (considered the negative control) received distilled water (10 mL/kg); while groups III, IV, V, and VI were treated with the C. giganteus extract at 34, 85, 170 and 340 mg/kg p.o, respectively; and the group VII (considered positive control) received sodium valproate at 300 mg/kg, i.p. After 40 min post-treatment, a single dose of n-methyl-scopolamine (1 mg/kg, i.p) was administered to animals of groups (II, III, IV, V, VI, VII) followed by pilocarpine (360 mg/kg, i.p). Animal of group I (normal group) received distilled water. Rats were further observed for 6 h to evaluate the severity and the duration of the acute seizures of epilepsy according to Racine scale. Anxious behavior status post-epilepticus was also assessed in the same rats used above in the Elevated Plus Maze and number of entries into the open or closed arms and the time spent on either open or closed arms of the platform were recorded. Animals were also evaluated on Open Field Test and the number of rearing, crossing, grooming, defecation and center time were registered. RESULTS: C. giganteus decoction significantly (P < 0.05) reduced the animal mortality, the number and duration of convulsions and effectively increased the latency of convulsions. The plant extract significantly (P < 0.05) improved GSH level and SOD activity, reduced MDA and CAT activity, increased GABA level and decreased GABA-t activity in hippocampus. The anxiety induced by pilocarpine was also significantly (P < 0.05) inhibited by the extract of the plant. CONCLUSIONS: Thus, C. giganteus has demonstrated its antiepileptic and anxiolytic activities in rat model and may be used as preventive measure for patients suffering from epilepsy seizures and anxiety.

Spontaneous recurrent seizures in an intra-amygdala kainate microinjection model of temporal lobe epilepsy are differentially sensitive to antiseizure drugs.

The discovery and development of novel antiseizure drugs (ASDs) that are effective in controlling pharmacoresistant spontaneous recurrent seizures (SRSs) continues to represent a significant unmet clinical need. The Epilepsy Therapy Screening Program (ETSP) has undertaken efforts to address this need by adopting animal models that represent the salient features of human pharmacoresistant epilepsy and employing these models for preclinical testing of investigational ASDs. One such model that has garnered increased interest in recent years is the mouse variant of the Intra-Amygdala Kainate (IAK) microinjection model of mesial temporal lobe epilepsy (MTLE). In establishing a version of this model, several methodological variables were evaluated for their effect(s) on pertinent quantitative endpoints. Although administration of a benzodiazepine 40 min after kainate (KA) induced status epilepticus (SE) is commonly used to improve survival, data presented here demonstrates similar outcomes (mortality, hippocampal damage, latency periods, and 90-day SRS natural history) between mice given midazolam and those that were not. Using a version of this model that did not interrupt SE with a benzodiazepine, a 90-day natural history study was performed and survival, latency periods, SRS frequencies and durations, and SRS clustering data were quantified. Finally, an important step towards model adoption is to assess the sensitivities or resistances of SRSs to a panel of approved and clinically used ASDs. Accordingly, the following ASDs were evaluated for their effects on SRSs in these mice: phenytoin (20 mg/kg, b.i.d.), carbamazepine (30 mg/kg, t.i.d.), valproate (240 mg/kg, t.i.d.), diazepam (4 mg/kg, b.i.d.), and phenobarbital (25 and 50 mg/kg, b.i.d.). Valproate, diazepam, and phenobarbital significantly attenuated SRS frequency relative to vehicle controls at doses devoid of observable adverse behavioral effects. Only diazepam significantly increased seizure freedom. Neither phenytoin nor carbamazepine significantly altered SRS frequency or freedom under these experimental conditions. These data demonstrate that SRSs in this IAK model of MTLE are pharmacoresistant to two representative sodium channel-inhibiting ASDs (phenytoin and carbamazepine) and partially sensitive to GABA receptor modulating ASDs (diazepam and phenobarbital) or a mixed-mechanism ASD (valproate). Accordingly, this model is being incorporated into the NINDS-funded ETSP testing platform for treatment resistant epilepsy.

Cnestis ferruginea Vahl ex DC (Connaraceae) downregulates expression of immediate early genes in kainic acid-induced temporal lobe epilepsy in mice.

OBJECTIVES: This study investigates the influence of Cnestis ferruginea (CF) on kainic acid (KA)-induced immediate early genes (IEGs) associated with hippocampal sclerosis in temporal lobe epilepsy (TLE) in mice. METHODS: Animals were randomly divided into preventive treatment; vehicle (10 mL/kg, p.o.) or CF (400 mg/kg, p.o.) for three consecutive days before KA (5 mg/kg, i.p.) on days 4 and 5. In the reversal model, KA (5 mg/kg, i.p.) was administered on days 1 and 2 before CF (400 mg/kg) administration on days 3-5. Animals were euthanized on day 5, 6 h after KA exposure in preventive model and 1 h after CF administration in reversal model to estimate markers of IEGs. RESULTS: KA upregulated the expression of c-Fos protein by 3.32-, 9.45-, 8.13-, and 8.66-fold in the hippocampal CA1, CA2, CA3, and DG regions, respectively. Also, KA elevated inducible nitric oxide synthase protein expression by 10.9-, 10.6-, 9.78-, and 9.51-fold. Besides, mRNA expression of brain-derived neurotrophic factors and heat shock protein was increased by 2.38- and 1.39-fold, respectively, after exposure to KA which were attenuated by CF. CONCLUSIONS: CF attenuated KA-induced IEGs and could be used as an adjunct in TLE.

Acupuncture, seizure frequency, and quality of life in temporal lobe epilepsy.

OBJECTIVE: To assess seizure frequency and quality of life (QOL) in a group of adults with temporal lobe epilepsy with hippocampal sclerosis (TLE-HS) before and after 10 weeks of systemic acupuncture sessions and compare the results with a group of patients with TLE-HS not undergoing acupuncture. METHODS: The Quality of Life in Epilepsy Inventory (QOLIE-31) and the initial and final seizure frequency of 26 adult patients with TLE-HS who underwent acupuncture sessions for 10 consecutive weeks were assessed. The data were compared to those of 26 patients with TLE-HS not submitted to acupuncture, with p < 0.05. RESULTS: There was a clinically significant effect in reducing the mean number of seizures per month in the follow-up period of patients submitted or not to acupuncture (no intervention group and intervention group, effect size: -0.94 and -1.01, respectively). In the last four weeks of follow-up, there was a significant difference between the no intervention and intervention groups (0.5 [0-2] and 0 [0-4]; p = 0.018). When using minimally important change (MIC) threshold data for the QOLIE-31 between the final and initial scores, with the Cantril Ladder Scale as anchoring, it was observed that, in the intervention group, large clinically significant effects were seen for all dimensions, except for cognitive function, medication effect, and social function, which presented medium effects. In the follow-up, the variation of the QOLIE-31 scores was positive for both groups; however, it was higher in all dimensions in the intervention group, indicating a better QOL. CONCLUSION: There was a reduction in the mean number of seizures per month in all patients during the follow-up period. Acupuncture significantly reduced the number of seizures in the intervention group in the final phase of the study. QOL improvements occurred in all patients, however, more significantly in the intervention group.

Stereotactic EEG-guided radiofrequency thermocoagulation versus anterior temporal lobectomy for mesial temporal lobe epilepsy with hippocampal sclerosis: study protocol for a randomised controlled trial.

INTRODUCTION: In this report, we aim to describe the design for the randomised controlled trial of Stereotactic electroencephalogram (EEG)-guided Radiofrequency Thermocoagulation versus Anterior Temporal Lobectomy for Mesial Temporal Lobe Epilepsy with Hippocampal Sclerosis (STARTS). Mesial temporal lobe epilepsy (mTLE) is a classical subtype of temporal lobe epilepsy that often requires surgical intervention. Although anterior temporal lobectomy (ATL) remains the most popular treatment for mTLE, accumulating evidence has indicated that ATL can cause tetartanopia and memory impairments. Stereotactic EEG (SEEG)-guided radiofrequency thermocoagulation (RF-TC) is a non-invasive alternative associated with lower seizure freedom but greater preservation of neurological function. In the present study, we aim to compare the safety and efficacy of SEEG-guided RF-TC and classical ATL in the treatment of mTLE. METHODS AND ANALYSIS: STARTS is a single-centre, two-arm, randomised controlled, parallel-group clinical trial. The study includes patients with typical mTLE over the age of 14 who have drug-resistant seizures for at least 2 years and have been determined via detailed evaluation to be surgical candidates prior to randomisation. The primary outcome measure is the cognitive function at the 1-year follow-up after treatment. Seizure outcomes, visual field abnormalities after surgery, quality of life, ancillary outcomes, and adverse events will also be evaluated at 1-year follow-up as secondary outcomes. DISCUSSION: SEEG-guided RF-TC for mTLE remains a controversial seizure outcome but has the advantage for cognitive and visual field protection. This is the first RCT studying cognitive outcomes and treatment results between SEEG-guided RF-TC and standard ATL for mTLE with hippocampal sclerosis. This study may provide higher levels of clinical evidence for the treatment of mTLE. TRIAL REGISTRATION: ClinicalTrials.gov NCT03941613 . Registered on May 8, 2019. The STARTS protocol has been registered on the US National Institutes of Health. The status of the STARTS was recruiting and the estimated study completion date was December 31, 2021.

Pergularia daemia hydro-ethanolic extract protects against pentylenetetrazole kindling-induced seizures, oxidative stress, and neuroinflammation in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Current antiepileptic drugs fail to control approximately 30% of epilepsies. Therefore, there is a need to develop more effective antiepileptic drugs, and medicinal plants provide an attractive source for new compounds. Pergularia daemia (Asclepiadaceae) is used in Cameroon traditional medicine to treat stroke, anemia, inflammation, and epilepsy. Recently, traditional healers claim that an hydro-ethanolic extract of the roots of P. daemia is more effective than an aqueous extract on refractory seizures. AIM OF THE STUDY: The antiepileptic effect of P. daemia hydro-ethanolic extract was investigated on the pentylenetetrazole kindling model of temporal lobe epilepsy in mice and possible mechanisms of action. MATERIALS AND METHODS: Mice were divided into 8 groups treated as follows: normal group received distilled water (10 ml/kg, p.o.), control group received distilled water (10 ml/kg, p.o.), ethanol group received ethanol (5%, p.o.), positive control received sodium valproate (300 mg/kg, p.o.), and test groups received P. daemia hydro-ethanolic (HE) extract (1.6, 4, 8 and 16 mg/kg, p.o.). All groups were kindled by 11 injections of pentylenetetrazole (PTZ) (35 mg/kg, i.p.), once every alternate day (48 ± 2 h), until the development of kindling, i.e., the occurrence of stage 5 seizures for two consecutive trials. One week later, i.e., 29th day, mice were challenged with a single and lower dose of PTZ (25 mg/kg, i.p.) that does not induce seizures in normal mice but causes seizures in mice prone to seizures and behavioral alterations. After completion of the kindling procedure, Morris water maze, passive avoidance, and open field tests were performed. Afterward, animals were euthanized, and hippocampi were removed for the estimation of the levels of GABA-transaminase (GABA-T), L-glutamate decarboxylase (L-GAD), and γ-aminobutyric acid (GABA). Oxidative stress and neuroinflammation markers also were quantified. Finally, histological analysis of the hippocampus was carried out. RESULTS: PTZ-kindling induced myoclonic jerks and generalized tonic-clonic seizures in control mice. However, the HE extract of P. daemia (4-16 mg/kg), compared to sodium valproate, significantly protected mice against myoclonic jerks and generalized tonic-clonic seizures. Also, the HE extract (1.6-16 mg/kg) significantly increased the seizure score. Furthermore, the HE extract of P. daemia significantly reduced seizure-induced cognitive impairments. PTZ-kindling induced significant alterations in GABA, GABA-T, and L-GAD contents as well as oxidative stress, and neuroinflammation, and the HE extract significantly reversed these effects, suggesting possible mechanisms. All these activities of the HE extract were confirmed by its protective effect against neuronal loss in the hippocampus. CONCLUSIONS: The HE extract of P. daemia protected mice against kindled seizures and cognitive impairments, and these effects were greater than those of sodium valproate, a widely used antiepileptic drug. These effects may be mediated by neuromodulatory, anti-oxidant, and anti-inflammatory activities, thus suggesting a neuroprotective effect. These findings help to explain the beneficial use of these HE extracts of P.daemia in traditional medicine to treat epilepsy in Cameroon.

Development of an antiepileptogenesis drug screening platform: Effects of everolimus and phenobarbital.

OBJECTIVE: The kainic acid (KA)-induced status epilepticus (SE) model in rats is a well-defined model of epileptogenesis. This model closely recapitulates many of the clinical and pathological characteristics of human temporal lobe epilepsy (TLE) that arise following SE or another neurological insult. Spontaneous recurrent seizures (SRS) in TLE can present after a latent period following a neurological insult (traumatic brain injury, SE event, viral infection, etc.). Moreover, this model is suitable for preclinical studies to evaluate the long-term process of epileptogenesis and screen putative disease-modifying/antiepileptogenic agents. The burden of human TLE is highly variable, similar to the post-KA SE rat model. In this regard, this model may have broad translational relevance. This report thus details the pharmacological characterization and methodological refinement of a moderate-throughput drug screening program using the post-KA-induced SE model of epileptogenesis in male Sprague Dawley rats to identify potential agents that may prevent or modify the burden of SRS. Specifically, we sought to demonstrate whether our protocol could prevent the development of SRS or lead to a reduced frequency/severity of SRS. METHODS: Rats were administered either everolimus (2-3 mg/kg po) beginning 1, 2, or 24 h after SE onset, or phenobarbital (60 mg/kg ip) beginning 1 h after SE onset. All treatments were administered once/day for 5-7 days. Rats in all studies (n = 12/treatment dose/study) were then monitored intermittently by video-electroencephalography (2 weeks on, 2 weeks off, 2 weeks on epochs) to determine latency to onset of SRS and disease burden. RESULTS: Although no adverse side effects were observed in our studies, no treatment significantly modified disease or prevented the presentation of SRS by 6 weeks after SE onset. SIGNIFICANCE: Neither phenobarbital nor everolimus administered at several time points after SE onset prevented the development of SRS. Nonetheless, we demonstrate a practical and moderate-throughput screen for potential antiepileptogenic agents in a rat model of TLE.