Investigation of in-vivo GABA+ and Glutamate levels in patients with drug resistant unilateral temporal lobe epilepsy using MEGA-PRESS and correlates with clinical semiology.

Editor's evaluation: Disease-modifying effects of sodium selenate in a model of drug-resistant, temporal lobe epilepsy

Temporal lobe epilepsy (TLE) is associated with smaller hippocampal volume and with elevated extracellular (EC) glutamate levels. We investigated the relationship between the hippocampal volume and glutamate in refractory TLE patients. We used quantitative MRI volumetrics to measure the hippocampal volume and zero-flow microdialysis to measure the interictal glutamate, glutamine, and GABA levels in the epileptogenic hippocampus of 17 patients with medication-resistant epilepsy undergoing intracranial EEG evaluation. The relationships between hippocampal volume, neurochemical levels, and relevant clinical factors were examined. Increased EC glutamate in the epileptogenic hippocampus was significantly related to smaller ipsilateral (R(2)= 0.75, p < 0.0001), but not contralateral hippocampal volume when controlled for glutamine and GABA levels, and for clinical factors known to influence hippocampal volume. Glutamate in the atrophic hippocampus was significantly higher (p = 0.008, n = 9), with the threshold for hippocampal atrophy estimated as 5 microM. GABA and glutamine levels in the atrophic and nonatrophic hippocampus were comparable. Decreased hippocampal volume was related to higher seizure frequency (p = 0.008), but not to disease duration or febrile seizure history. None of these clinical factors were related to the neurochemical levels. We provide evidence for a significant association between increased EC glutamate and decreased ipsilateral epileptogenic hippocampal volume in TLE. Future work will be needed to determine whether the increase in glutamate has a causal relationship with hippocampal atrophy, or whether another, yet unknown factor results in both. This work has implications for the understanding and treatment of epilepsy as well as other neurodegenerative disorders associated with hippocampal atrophy.

Introduction. In patients with drug-resistant temporal lobe epilepsy (TLE), surgical treatment is aimed to resect an epileptogenic zone (EZ) followed by seizure control. Despite complicated EZ location, surgical resection should be considered as a treatment of choice in bilateral TLE. Objective: to evaluate surgical outcomes and factors contributing to outcomes in patients with drug-resistant bilateral TLE confirmed via magnetic resonance imaging. Materials and methods. The study included patients with unilateral (n = 50) and bilateral (n = 50) temporal lobe involvement. The results of surgical treatment were evaluated according to the classification of J. Engel (1993). Results. Favorable outcomes of surgical treatment (Engel I and Engel II) in the group with unilateral temporal lobe involvement were found in 98% of patients after 12 months, in 88% after 24 months, and in 100% after 48 and 60 months after surgery. In the group with bilateral temporal lobe involvement outcomes of surgical treatment were favorable in 41% of patients after 12 months, in 50% after 24 months, in 39% after 48 months, and in 50% of patients after 60 months post-surgery. Conclusion. Early onset, burdened perinatal history, and MRI-confirmed left temporal lobe involvement contribute to the poor outcome (Engel III and Engel IV) in the bilateral TLE group. Engel I outcomes were more common in the patients with unilateral TLE while Engel IIIV outcomes were more common in the patients with bilateral TLE.

Epilepsy is a common disorder that affects the nervous systems of 1% of worldwide population. In epilepsy, one-third of patients are unresponsive to current drug therapies and develop drug-resistant epilepsy. Alterations in ghrelin, nesfatin-1, and irisin levels with epilepsy were reported in previous studies. Vasoactive intestinal peptide is among the most common neuropeptides in the hippocampus, which is the focus of the seizures in temporal lobe epilepsy. However, there is also lack of evidence of whether these four neuropeptide levels are altered with drug resistant temporal lobe epilepsy or not. The aim herein was the evaluation of the serum levels of nesfatin-1, ghrelin, irisin, and Vasoactive intestinal peptide in drug-resistant temporal lobe epilepsy patients and temporal lobe epilepsy (TLE) without drug resistance, and to compare them to healthy controls. This cross-sectional study group included 58 temporal lobe epilepsy patients (24 with drug resistant temporal lobe epilepsy and 34 with temporal lobe epilepsy who were not drug-resistant) and 28 healthy subjects. Nesfatin-1, ghrelin, irisin, and Vasoactive intestinal peptide serum levels were determined using enzyme-linked immunosorbent assay. The serum ghrelin levels of patients with drug resistant temporal lobe epilepsy were seen to have significantly decreased when compared to those of the control group (p<0.05). Serum nesfatin-1, vasoactive intestinal peptide, and irisin levels were seen to have decreased in the drug resistant temporal lobe epilepsy group when compared to those of the control and temporal lobe epilepsy groups; however, the difference was non-significant (p>0.05). The results herein suggested that ghrelin might contribute to the pathophysiology of drug resistant temporal lobe epilepsy. However, further studies are needed to confirm this hypothesis.

MRI morphology of the hippocampus in drug-resistant temporal lobe epilepsy: Shape inflation of left hippocampus and correlation of right-sided hippocampal volume and shape with visuospatial function in patients with right-sided TLE

Objective: To analyse the long term results of temporal lobe epilepsy surgery in a national epilepsy surgery centre for adults, and to evaluate preoperative factors predicting a good postoperative outcome...

The effects of local perfusion with the glutamate receptor agonist NMDA and the noncompetitive NMDA receptor antagonist dizolcipine (MK-801) on extracellular dopamine (DA), GABA, and glutamate (Glu) levels in the dorsolateral striatum were monitored using in vivo microdialysis in the halothane-anesthetized rat. In addition, the sensitivity of both the basal and NMDA-induced increases in levels of these neurotransmitter substances to perfusion with tetrodotoxin (TTX: 10(-5) M) and a low Ca2+ concentration (0.1 mM) was studied. The results show that the local perfusion (10 min) with both the 10(-3) and 10(-4) M dose of NMDA increased striatal DA and GABA outflow, whereas only the (10(-3) M) dose of NMDA was associated with a small and delayed increase in extracellular Glu levels. The NMDA-induced effects were dose-dependently counteracted by simultaneous perfusion with MK-801 (10(-6) and 10(-5) M). Both the basal and NMDA (10(-3) M)-induced increase in extracellular striatal DA content was reduced in the presence of TTX and a low Ca2+ concentration, whereas both basal and NMDA-stimulated GABA levels were unaffected by these treatments. Both the basal and NMDA-stimulated Glu levels were enhanced following TTX treatment, whereas perfusion with a low Ca2+ concentration reduced basal Glu levels and enhanced and prolonged the NMDA-induced stimulation. These data support the view that NMDA receptor stimulation plays a role in the regulation of extracellular DA, GABA, and Glu levels in the dorso-lateral neostriatum and provide evidence for a differential effect of NMDA receptor stimulation on these three striatal neurotransmitter systems, possibly reflecting direct and indirect actions mediated via striatal NMDA receptors.

Selective amygdalohippocampectomy versus standard temporal lobectomy in patients with mesial temporal lobe epilepsy and unilateral hippocampal sclerosis

Epilepsy surgery is the recommended treatment option for patients with drug-resistant temporal lobe epilepsy (TLE). This method offers a good chance of seizure freedom but carries a considerable risk of postoperative language impairment. The extremely variable neurocognitive profiles in surgical epilepsy patients cannot be fully explained by extent of resection, fiber integrity, or current task-based functional MRI (fMRI). In this study, the authors aimed to investigate pathology- and surgery-triggered language organization in TLE by using fMRI activation and network analysis as well as considering structural and neuropsychological measures. Twenty-eight patients with unilateral TLE (16 right, 12 left) underwent T1-weighted imaging, diffusion tensor imaging, and task-based language fMRI pre- and postoperatively (n = 15 anterior temporal lobectomy, n = 11 selective amygdalohippocampectomy, n = 2 focal resection). Twenty-two healthy subjects served as the control cohort. Functional connectivity, activation maps, and laterality indices for language dominance were analyzed from fMRI data. Postoperative fractional anisotropy values of 7 major tracts were calculated. Naming, semantic, and phonematic verbal fluency scores before and after surgery were correlated with imaging parameters. fMRI network analysis revealed widespread, bihemispheric alterations in language architecture that were not captured by activation analysis. These network changes were found preoperatively and proceeded after surgery with characteristic patterns in the left and right TLEs. Ipsilesional fronto-temporal connectivity decreased in both left and right TLE. In left TLE specifically, preoperative atypical language dominance predicted better postoperative verbal fluency and naming function. In right TLE, left frontal language dominance correlated with good semantic verbal fluency before and after surgery, and left fronto-temporal language laterality predicted good naming outcome. Ongoing seizures after surgery (Engel classes ID-IV) were associated with naming deterioration irrespective of seizure side. Functional findings were not explained by the extent of resection or integrity of major white matter tracts. Functional connectivity analysis contributes unique insight into bihemispheric remodeling processes of language networks after epilepsy surgery, with characteristic findings in left and right TLE. Presurgical contralateral language recruitment is associated with better postsurgical language outcome in left and right TLE.

Mesial temporal lobe epilepsy (mTLE) is an important cause of drug-resistant epilepsy (DRE) in adults and children. Traditionally, the surgical option of choice for mTLE includes a frontotemporal craniotomy and open resection of the anterior temporal cortex and mesial temporal structures. Although this technique is effective and durable, the neuropsychological morbidity resulting from temporal neocortical resections has resulted in the investigation of alternative approaches to resect the mesial temporal structures to achieve seizure freedom while minimizing postoperative cognitive deficits. Outcomes supporting the use of selective temporal resections have resulted in alternative approaches to directly access the mesial temporal structures via endoscopic approaches whose direct trajectory to the epileptogenic zone minimizes retraction, resection, and manipulation of surrounding cortex. The authors reviewed the utility of the endoscopic transmaxillary, endoscopic endonasal, endoscopic transorbital, and endoscopic supracerebellar transtentorial approaches for the treatment of drug-resistant mesial temporal lobe epilepsy. First, a review of the literature demonstrated the anatomical feasibility of each approach, including the limits of exposure provided by each trajectory. Next, clinical data assessing the safety and effectiveness of these techniques in the treatment of DRE were analyzed. An outline of the surgical techniques is provided to highlight the technical nuances of each approach. The direct access to mesial temporal structures and avoidance of lateral temporal manipulation makes endoscopic approaches promising alternatives to traditional methods for the treatment of DRE arising from the temporal pole and mesial temporal lobe. A dearth of literature outlining clinical outcomes, a need for qualified cosurgeons, and a lack of experience with endoscopic approaches remain major barriers to widespread application of the aforementioned techniques. Future studies are warranted to define the utility of these approaches moving forward.

Objective: Metabolic abnormality in the extratemporal area on fluorine-18-fluorodeoxyglucose positron emission tomography (FDG-PET) is not an uncommon finding in drug-resistant temporal lobe epilepsy (TLE), however the correlation between extratemporal metabolic abnormalities and surgical long-term prognosis has not been fully elucidated. We aim to investigate FDG-PET extratemporal metabolic profiles predictive of failure in surgery for TLE patients.Methods: Eighty-two patients with unilateral TLE (48 female, 34 male; 25.6 ± 10.6 years old; 37 left TLE, 45 right TLE) and 30 healthy age-matched controls were enrolled. Patients were classified either as experiencing seizure-recurrence (SZR, Engel class II through IV) or seizure-free (SZF, Engel class I) at least 1 year after surgery. Regional cerebral metabolism was evaluated by FDG-PET with statistical parametric mapping (SPM12). Abnormal metabolic profiles and patterns on FDG-PET in SZR group were evaluated and compared with those of healthy control and SZF subjects on SPM12. Volume and intensity as well as special brain areas of abnormal metabolism in temporal and extratemporal regions were quantified and visualized.Results: With a median follow-up of 1.5 years, 60% of patients achieved Engel class I (SZF). SZR was associated with left TLE and widespread hypometabolism in FDG-PET visual assessment (both p < 0.05). All patients had hypometabolism in the ipsilateral temporal lobe but SZR was not correlated with volume or intensity of temporal hypometabolism (median, 1,456 vs. 1,040 mm3; p > 0.05). SZR was correlated with extratemporal metabolic abnormalities that differed according to lateralization: in right TLE, SZR exhibited larger volume in extratemporal areas compared to SZF (median, 11,060 vs. 2,112 mm3; p < 0.05). Surgical failure was characterized by Cingulum_Ant_R/L, Frontal_Inf_Orb_R abnormal metabolism in extratemporal regions. In left TLE, SZR presented a larger involvement of extratemporal areas similar to right TLE but with no significant (median, 5,873 vs. 3,464 mm3; p > 0.05), Cingulum_Ant_ R/L, Parietal_Inf_L, Postcentral_L, and Precuneus_R involved metabolic abnormalities were correlated with SZR.Conclusions: Extratemporal metabolic profiles detected by FDG-PET may indicate a prominent cause of TLE surgery failure and should be considered in predictive models for epilepsy surgery. Seizure control after surgery might be improved by investigating extratemporal areas as candidates for resection or neuromodulation.

Mismatch negativity is abnormal but not lateralizing in temporal lobe epilepsy.

Patients with non-lesional or bilateral temporal-lobe epilepsy (TLE) are often excluded from surgical treatment. This study investigated focus lateralization in TLE to understand identification of the affected hemisphere with regard to non-lesional or bilateral affection and postsurgical outcome. A total of 24 TLE patients underwent presurgical evaluation with magnetic resonance imaging (MRI), proton magnetic resonance spectroscopy (1H-MRS), video-electroencephalogram (video-EEG), and/or intracranial EEG (icEEG), and they were classified as MRI-positive or negative, unilateral or bilateral TLE cases. In patients with positive-MRI, MRI and 1H-MRS indicated high (100%) concordant lateralization to EEG findings in unilateral TLE, and moderate (75%) concordance to icEEG findings in bilateral TLE; whereas in patients with negative-MRI, 1H-MRS indicated moderate (60%–75%) concordance to EEG and/or icEEG in unilateral TLE, and relatively low (50%) concordance to icEEG in bilateral TLE. Ninety point nine percent of patients with unilateral TLE and 41.7% of patients with bilateral TLE (including 50% of MRI-negative bilateral TLE) became seizure-free. The MRS findings were not correlated with seizure outcome, while non-seizure-free patients had an insignificantly higher percentage of contralateral N-acetyl aspartate (NAA) reduction compared with seizure-free patients, indicating the relatively low predictive value of 1H-MRS for surgical outcome. Further, EEG and icEEG findings were significantly correlated with seizure outcome, and for patients with positive MRI, MRI findings were also correlated with seizure outcome, indicating the predictive value of these modalities. The results suggested that a multimodal approach including neuroimaging, EEG, and/or icEEG could identify seizure focus in most cases, and provide surgical options for non-lesional or bilateral TLE patients with a possible good outcome.

<h3>Objective:</h3> To determine the long-term seizure freedom and resolution of epilepsy in patients with drug resistant Temporal Lobe Epilepsy (TLE) and a clear-cut MRI lesion. <h3>Background:</h3> The long-term seizure free outcomes following surgery for TLE varied widely from 41% – 80% following surgery for TLE. <h3>Design/Methods:</h3> In a retrospective, longitudinal cohort study, we analysed the presurgical, surgical and post-surgical parameters to determine the seizure freedom and resolution of epilepsy in patients with ‘drug resistant lesional TLE with at least 10 years or more of post-surgery follow-up. The Study period was from June 2001 to 2012 <h3>Results:</h3> Of the 259 patients who formed the study population, 46% were women. The duration of follow-up ranged from 10 to 21 years. The average age at surgery was 25.80 ± 11.32 yrs; 49% had an aura, 61% had only hypomotor seizures and 38% had psychiatric comorbidity. The commonest pathology was hippocampal sclerosis(70%) followed by tumoral lesions and focal cortical dysplasia; 9.8% had acute post-operative seizures. At latest follow-up 75.6% were seizure free of which 52% had resolution of epilepsy. Presence of an aura , hippocampal sclerosis and longer time to first post-operative seizure were strong predictors for resolution of epilepsy while acute post-operative seizures and an abnormal post-surgery EEG at 1 year were predictors of persistent seizures. On survival analysis, the time to first seizure was significantly early in patients with persistent seizures. Seizure freedom both at three and five years predicted seizure freedom at 10 years. <h3>Conclusions:</h3> Resective surgery for drug resistant lesional TLE was associated with higher rate of seizure-freedom in ~75% and resolution of epilepsy in 52.15% even at long term follow-up. Longer time to first seizure, presence of aura at presentation and hippocampal sclerosis are strong predictors for resolution of epilepsy. APOS and abnormal Post-Surgery inter-ictal EEG are predictors of unfavourable outcome. <b>Disclosure:</b> Dr. Sattaluri has nothing to disclose. Dr. Patil has nothing to disclose. Dr. Choudhary has nothing to disclose. Dr. Vooturi has nothing to disclose.

A high proportion of patients with drug-resistant temporal lobe epilepsy (TLE) show focal relative hypometabolism in the region of the epileptogenic zone on [18F]-Fluorodeoxyglucose positron emission tomography (FDG PET). However, whether focal (hypo)metabolism changes over time has not been well studied. We analysed repeated [18F]-FDG PET scans of patients with TLE to determine longitudinal changes in glucose metabolism. Adults (n = 16; 9 female, 7 male) diagnosed with drug resistant chronic TLE were assessed. Each patient had two [18F]-FDG PET scans that were 2-95months apart. Region-of-interest analysis was performed on MR images onto which PET scans were coregistered to determine the relative [18F]-FDG uptake (normalised to pons) in the bilateral hippocampi and temporal lobes. Statistical Parametric Mapping analysis investigated global voxel-wise changes in relative metabolism between timepoints. Normalised [18F]-FDG uptake did not change with time in the ipsilateral (baseline 1.14 ± 0.03, follow-up 1.19 ± -0.04) or contralateral hippocampus (baseline 1.18 ± 0.03, follow-up 1.19 ± 0.03). Uptake in the temporal neocortex also remained stable (ipsilateral baseline 1.35 ± 0.03, follow-up 1.30 ± 0.04; contralateral baseline 1.38 ± 0.04, follow-up 1.33 ± 0.03). The was no relationship between change in uptake on the repeated scans and the time between the scans. SPM analysis showed increases in metabolism in the ipsilateral temporal lobe in 2/16 patients. No areas of decreased metabolism concordant to the epileptogenic zone were identified. [18F]-FDG uptake showed no significant changes over time in patients with drug-resistant TLE. This suggests that repeating FDG-PET scans in patients with subtle or no hypometabolism is of low clinical yield.