Evaluating the Contributions of State of the Art Assessment Techniques to Predicting Memory Outcome after Unilateral Anterior Temporal Lobectomy

Purpose:Although anterior temporal lobectomy (ATL) is an effective treatment for many patients with medically refractory temporal lobe epilepsy (TLE), one risk associated with this procedure is postsurgical decline in memory. A substantial number of past studies examined factors that predict memory decline after surgery, but few have investigated multiple predictors simultaneously or considered measures that are currently in use. Methods: This study compared the relative contributions made by presurgical neuropsychological test scores, MRI-based hippocampal volumetric analysis, and Wada test results to predicting memory outcome after ATL in a group of 87 patients. Results: Logistic regression analyses indicated that noninvasive procedures (neuropsychological testing and MRI) made significant contributions to improving the prediction of memory outcome in this sample. The results from the Wada procedure did not significantly improve prediction once these other factors were considered. The only exception was in predicting memory for visual information after a delay, in which Wada results improved prediction accuracy from 78% to 81%. Conclusions: Current neuropsychological tests and MRI volumetric measures predict changes in verbal and visual memory after ATL. The relatively small change in correct classification rates when Wada memory scores are considered calls into question the benefits of using Wada test results to predict memory outcome when the results of noninvasive procedures are available

Significance of MDR1 and multiple drug resistance in refractory human epileptic brain

BACKGROUND: The multiple drug resistance protein (MDR1/P-glycoprotein) is overexpressed in glia and blood-brain barrier (BBB) endothelium in drug refractory human epileptic tissue. Since various antiepileptic drugs (AEDs) can act as substrates for MDR1, the enhanced expression/function of this protein may increase their active extrusion from the brain, resulting in decreased responsiveness to AEDs. METHODS: Human drug resistant epileptic brain tissues were collected after surgical resection. Astrocyte cell cultures were established from these tissues, and commercially available normal human astrocytes were used as controls. Uptake of fluorescent doxorubicin and radioactive-labeled Phenytoin was measured in the two cell populations, and the effect of MDR1 blockers was evaluated. Frozen human epileptic brain tissue slices were double immunostained to locate MDR1 in neurons and glia. Other slices were exposed to toxic concentrations of Phenytoin to study cell viability in the presence or absence of a specific MDR1 blocker. RESULTS: MDR1 was overexpressed in blood vessels, astrocytes and neurons in human epileptic drug-resistant brain. In addition, MDR1-mediated cellular drug extrusion was increased in human 'epileptic' astrocytes compared to 'normal' ones. Concomitantly, cell viability in the presence of cytotoxic compounds was increased. CONCLUSIONS: Overexpression of MDR1 in different cell types in drug-resistant epileptic human brain leads to functional alterations, not all of which are linked to drug pharmacokinetics. In particular, the modulation of glioneuronal MDR1 function in epileptic brain in the presence of toxic concentrations of xenobiotics may constitute a novel cytoprotective mechanism

Quantitative positron emission tomography-guided magnetic resonance imaging postprocessing in magnetic resonance imaging-negative epilepsies

Objective: Detection of focal cortical dysplasia (FCD) is of paramount importance in epilepsy presurgical evaluation. Our study aims at utilizing quantitative positron emission tomography (QPET) analysis to complement magnetic resonance imaging (MRI) postprocessing by a morphometric analysis program (MAP) to facilitate automated identification of subtle FCD. Methods: We retrospectively included a consecutive cohort of surgical patients who had a negative preoperative MRI by radiology report. MAP was performed on T1-weighted volumetric sequence and QPET was performed on PET/computed tomographic data, both with comparison to scanner-specific normal databases. Concordance between MAP and QPET was assessed at a lobar level, and the significance of concordant QPET-MAP(+) abnormalities was confirmed by postresective seizure outcome and histopathology. QPET thresholds of standard deviations (SDs) of -1, -2, -3, and -4 were evaluated to identify the optimal threshold for QPET-MAP analysis. Results: A total of 104 patients were included. When QPET thresholds of SD = -1, -2, and -3 were used, complete resection of the QPET-MAP(+) region was significantly associated with seizure-free outcome when compared with the partial resection group (P = 0.023, P <0.001, P = 0.006) or the no resection group (P = 0.002, P <0.001, P = 0.001). The SD threshold of -2 showed the best combination of positive rate (55%), sensitivity (0.68), specificity (0.88), positive predictive value (0.88), and negative predictive value (0.69). Surgical pathology of the resected QPET-MAP(+) areas revealed mainly FCD type L Multiple QPETMAP(+) regions were present in 12% of the patients at SD = -2. Significance: Our study demonstrates a practical and effective approach to combine quantitative analyses of functional (QPET) and structural (MAP) imaging data to improve identification of subtle epileptic abnormalities. This approach can he readily adopted by epilepsy centers to improve postresective seizure outcomes for patients without apparent lesions on MRI.Peer reviewe

Inducible deletion of CD28 prior to secondary nippostrongylus brasiliensis infection impairs worm expulsion and recall of protective memory CD4 (+) T cell responses

IL-13 driven Th2 immunity is indispensable for host protection against infection with the gastrointestinal nematode Nippostronglus brasiliensis. Disruption of CD28 mediated costimulation impairs development of adequate Th2 immunity, showing an importance for CD28 during the initiation of an immune response against this pathogen. In this study, we used global CD28−/− mice and a recently established mouse model that allows for inducible deletion of the cd28 gene by oral administration of tamoxifen (CD28−/loxCre+/−+TM) to resolve the controversy surrounding the requirement of CD28 costimulation for recall of protective memory responses against pathogenic infections. Following primary infection with N. brasiliensis, CD28−/− mice had delayed expulsion of adult worms in the small intestine compared to wild-type C57BL/6 mice that cleared the infection by day 9 post-infection. Delayed expulsion was associated with reduced production of IL-13 and reduced serum levels of antigen specific IgG1 and total IgE. Interestingly, abrogation of CD28 costimulation in CD28−/loxCre+/− mice by oral administration of tamoxifen prior to secondary infection with N. brasiliensis resulted in impaired worm expulsion, similarly to infected CD28−/− mice. This was associated with reduced production of the Th2 cytokines IL-13 and IL-4, diminished serum titres of antigen specific IgG1 and total IgE and a reduced CXCR5+ TFH cell population. Furthermore, total number of CD4+ T cells and B220+ B cells secreting Th1 and Th2 cytokines were significantly reduced in CD28−/− mice and tamoxifen treated CD28−/loxCre+/− mice compared to C57BL/6 mice. Importantly, interfering with CD28 costimulatory signalling before re-infection impaired the recruitment and/or expansion of central and effector memory CD4+ T cells and follicular B cells to the draining lymph node of tamoxifen treated CD28−/loxCre+/− mice. Therefore, it can be concluded that CD28 costimulation is essential for conferring host protection during secondary N. brasiliensis infection

The gamma band effect for episodic memory encoding is absent in epileptogenic hippocampi

Objective: The analysis of hippocampal local field potentials in humans during the encoding of episodic memories has revealed that a robust increase in gamma band oscillatory power predicts successful item encoding, termed the gamma band subsequent memory effect (SME). No previous investigation has looked for differences in this pattern between epileptogenic and non-epileptogenic sources; we sought to examine the gamma band effect in seizure patients to address this question.Methods: We recorded hippocampal activity in nine patients who underwent stereoelectroencephalography for seizure localization and also performed the Free Recall task, a standard test of episodic memory. We compared gamma band oscillatory activity between 15 electrodes localized to epileptogenic hippocampi and 24 electrodes in non-epileptogenic hippocampi.Results: The epileptogenic hippocampi exhibited a significant decrease in gamma band power during successful item encoding, whereas the non-epileptogenic group exhibited the expected positive gamma band effect (t(37) = 4.69, p < 0.0001).Conclusions: The typical gamma band effect is reversed for epileptogenic hippocampi. Significance: This is the first study to demonstrate a difference for epileptogenic hippocampi for an important oscillatory pattern that normally predicts successful item encoding. Patients with epilepsy suffer selective impairment of episodic memory ability, so our findings are especially relevant for clinicians and memory researchers alike. (C) 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved

Paradoxical ictal EEG lateralization in children with unilateral encephaloclastic lesions

Background. Describe an ictal EEG pattern of paradoxical lateralization in children with unilateral encephaloclastic hemispheric lesion acquired early in life. Methods. of 68 children who underwent hemispherectomy during 2003-2005, scalp video-EEG and brain MRI of six children with an ictal scalp EEG pattern discordant to the clinical and imaging data were reanalyzed. Medical charts were reviewed for clinical findings and seizure outcome. Results. Age of seizure onset was 1 day-4 years. the destructive MRI lesion was an ischemic stroke in 2, a post-infectious encephalomalacia in 2, and a perinatal trauma and hemiconvulsive-hemiplegic syndrome in one patient each. Ictal EEG pattern was characterized by prominent ictal rhythms with either 3-7 Hz spike and wave complexes or beta frequency sharp waves (paroxysmal fast) over the unaffected (contralesional) hemisphere. Scalp video-EEG was discordant, however, other findings of motor deficits (hemiparesis; five severe, one mild), seizure semiology (4/6), interictal EEG abnormalities (3/6), and unilateral burden of MRI lesion guided the decision for hemispherectomy. After 12-39 months of post-surgery follow up, five of six patients were seizure free and one has brief staring spells. Conclusion. We describe a paradoxical lateralization of the EEG to the good hemisphere in children with unihemispheric encephaloclastic lesions. This EEG pattern is compatible with seizure free outcome after surgery, provided other clinical findings and tests are concordant with origin from the abnormal hemisphere.Cleveland Clin Fdn, Neurol Inst, Epilepsy Ctr, Cleveland, OH 44195 USAUniversidade Federal de São Paulo, São Paulo, BrazilUniv Hosp Cleveland, Epilepsy Ctr, Cleveland, OH 44106 USAUniversidade Federal de São Paulo, São Paulo, BrazilWeb of Scienc

Epilepsies Associated With Hippocampal Sclerosis.

Hippocampal sclerosis (HS) is considered the most frequent neuropathological finding in patients with mesial temporal lobe epilepsy (MTLE). Hippocampal specimens of pharmacoresistant MTLE patients that underwent epilepsy surgery for seizure control reveal the characteristic pattern of segmental neuronal cell loss and concomitant astrogliosis. However, classification issues of hippocampal lesion patterns have been a matter of intense debate. International consensus classification has only recently provided significant progress for comparisons of neurosurgical and clinic-pathological series between different centers. The respective four-tiered classification system of the International League Against Epilepsy subdivides HS into three types and includes a term of gliosis only, no-HS. Future studies will be necessary to investigate whether each of these subtypes of HS may be related to different etiological factors or with postoperative memory and seizure outcome. Molecular studies have provided potential deeper insights into the pathogenesis of HS and MTLE on the basis of epilepsy-surgical hippocampal specimens and corresponding animal models. These include channelopathies, activation of NMDA receptors, and other conditions related to Ca(2+) influx into neurons, the imbalance of Ca(2+)-binding proteins, acquired channelopathies that increase neuronal excitability, paraneoplastic and non-paraneoplastic inflammatory events, and epigenetic regulation promoting or facilitating hippocampal epileptogenesis. Genetic predisposition for HS is clearly suggested by the high incidence of family history in patients with HS, and by familial MTLE with HS. So far, it is clear that HS is multifactorial and there is no individual pathogenic factor either necessary or sufficient to generate this intriguing histopathological condition. The obvious variety of pathogenetic combinations underlying HS may explain the multitude of clinical presentations, different responses to clinical and surgical treatment. We believe that the stratification of neuropathological patterns can help to characterize specific clinic-pathological entities and predict the postsurgical seizure control in an improved fashion.12821-3

Extra operative intracranial EEG monitoring for epilepsy surgery in elderly patients

Object: The objective of the study is to investigate and report our experience with extra operative intracranial EEG monitoring for evaluation of epilepsy surgery among elderly (≥60 years) patients. Methods: After IRB approval, we searched our prospectively maintained epilepsy surgery database to find patients who underwent eiEEG at the age of 60 years or older. Electronic medical records were reviewed to extract clinical and surgery-related information. Patients who underwent resective epilepsy surgery after eiEEG and had at least 1 year of clinical follow-up were assessed for seizure outcome. Categorical and continuous variables were compared using Pearson chi-square and Student's t-test, respectively. Results: A total of 21 patients, with 13 (62%) women, underwent eiEEG in our center at the age of 60 years or older. The mean age at time of implantation was 63.8 ± 2.7 years. Sub-dural grids (SDG) were implanted in five (24%) patients, whereas sixteen (76%) patients underwent stereo-EEG (SEEG) implantation. Median number of contacts in SDG were 106 (56–136) and depth electrodes in SEEG were 12 (9–14). There were 2 complications, including one mortality due to intracerebral hemorrhage. Sixteen (76%) patients underwent respective epilepsy surgery after eiEEG and eleven (69%) achieved Engel class I outcome on the last follow-up [mean follow-up duration of 2.7 (± 1.8) years]. Conclusion: We noticed an increased utilization of eiEEG in elderly patients after the introduction of SEEG at our center. Overall, we found that eiEEG can help achieve good seizure outcomes in the elderly population. However, the one eiEEG-related mortality serves a word of caution about the potential risks in this population. Keywords: Epilepsy surgery, Elderly, Intracranial recording, SEEG, Subdural electrodes, Outcom

Glucocorticoid Receptor β Isoform Predominates in the Human Dysplastic Brain Region and Is Modulated by Age, Sex, and Antiseizure Medication

The glucocorticoid receptor (GR) at the blood–brain barrier (BBB) is involved in the pathogenesis of drug-resistant epilepsy with focal cortical dysplasia (FCD); however, the roles of GR isoforms GRα and GRβ in the dysplastic brain have not been revealed. We utilized dysplastic/epileptic and non-dysplastic brain tissue from patients who underwent resective epilepsy surgery to identify the GRα and GRβ levels, subcellular localization, and cellular specificity. BBB endothelial cells isolated from the dysplastic brain tissue (EPI-ECs) were used to decipher the key BBB proteins related to drug regulation and BBB integrity compared to control and transfected GRβ-overexpressed BBB endothelial cells. GRβ was upregulated in dysplastic compared to non-dysplastic tissues, and an imbalance of the GRα/GRβ ratio was significant in females vs. males and in patients > 45 years old. In EPI-ECs, the subcellular localization and expression patterns of GRβ, Hsp90, CYP3A4, and CYP2C9 were consistent with GRβ+ brain endothelial cells. Active matrix metalloproteinase levels and activity increased, whereas claudin-5 levels decreased in both EPI-ECs and GRβ+ endothelial cells. In conclusion, the GRβ has a major effect on dysplastic BBB functional proteins and is age and gender-dependent, suggesting a critical role of brain GRβ in dysplasia as a potential biomarker and therapeutic target in epilepsy