MicroRNAs miR-629-3p, miR-1202 and miR-1225-5p as potential diagnostic and surgery outcome biomarkers for mesial temporal lobe epilepsy with hippocampal sclerosis.

BACKGROUND: Mesial temporal lobe epilepsy (MTLE) is a symptomatic epilepsy syndrome clinically characterized by high prevalence, pharmacoresistance, good surgical prognosis and hippocampal sclerosis (HS); however, no singular criteria can be considered sufficient for the MTLE-HS diagnosis. MicroRNAs (miRNAs) are small non-coding molecules that act as important gene-expression regulators at post-transcriptional level. Evidences on the involvement of miRNAs in epilepsy pathogenesis as well as their potential to be employed as biomarkers claim for investigations on miRNAs' applicability as epilepsy diagnosis and prognosis biomarkers. Consequently, the present study aimed to evaluate the applicability of three specific miRNAs as biomarkers of diagnosis and surgical outcomes in adult patients with MTLE-HS. METHOD: Hippocampus, amygdala and blood samples from 20 patients with MTLE-HS were analyzed, 10 with favorable surgical prognosis (Engel I) and 10 with unfavorable surgical prognosis (Engel III-IV). For the control groups, hippocampus and amygdala from necropsy and blood samples from healthy individuals were adopted. The miRNAs expression analysis was performed using Real-Time Quantitative Polymerase Chain Reaction for miRNAs highlighted from microarray as being involved in GABAergic neurotransmission. RESULTS: The miRNAs miR-629-3p, miR-1202 and miR-1225-5p were found to be hyper-expressed in MTLE-HS patients' blood. CONCLUSIONS: Our data suggest the existence of three circulating miRNAs (miR-629-3p, miR-1202 and miR-1225-5p) that could possibly act as additional tools in the set of factors that contribute to MTLE-HS diagnose.

Impacto de la cirugía de la epilepsia infantil en el rendimiento intelectual / Impact of pediatric epilepsy surgery on intellectual efficiency

Introducción. La cirugía de la epilepsia podría ser una opción terapéutica muy prometedora para el control de las crisis en pacientes con crisis refractarias que no responden a la medicación. Otro factor importante a favor de la opción quirúrgica son los resultados cognitivos. Objetivo. Investigar la correlación entre los resultados tanto de las crisis como cognitivos tras la cirugía para tratar la epilepsiaen una población pediátrica.Pacientes y métodos. Se evaluó de manera retrospectiva a un total de 59 pacientes pediátricos antes y al menos seis meses después de la cirugía mediante la tercera edición de la escala de inteligencia para niños de Wechsler (escala global, escala verbal y escala manipulativa). Se dividió a los pacientes en dos grupos en función de la presencia o ausencia de la mejoría del control de las crisis tras la cirugía. Los datos que se recogían de cada niño incluían: tipo de epilepsia, etiología, edad de comienzo de la epilepsia, duración de la epilepsia y frecuencia de las crisis.Resultados. Al comparar los datos mediante un análisis multivariado de la varianza se observaron diferencias significativas en las escalas global, verbal y manipulativa preoperatorias (p = 0,01) con unos resultados mejores en el grupo con reducción de las crisis que en el grupo sin reducción de las crisis. El grupo con mejoría de las crisis consiguió una mejoría significativa en la escala manipulativa (p = 0,01) y el grupo sin mejoría de las crisis obtuvo un empeoramiento significativoen la escala verbal (p = 0,01).Conclusiones. Nuestros resultados sugieren que el éxito de la cirugía para el tratamiento de la epilepsia en la infancia cuando se logra un control de las crisis podría conllevar también una mejoría en la escala manipulativa, mientras que lapersistencia de las crisis podría empeorar la escala verbal (AU)

Introduction. Epilepsy surgery may be a promising alternative therapy for seizure control in patients with refractory seizures, resistant to medication. Cognitive outcome is another important factor in favor of the surgical decision. Aim. To investigate the correlation between seizure outcome and cognitive outcome after epilepsy surgery in a pediatric population. Patients and methods. A total of 59 pediatric patients were retrospectively assessed with the WISC-III (Full Scale, Verbal Scale and Performance Scale) before and, at least, 6 months after surgery. Patients were divided into two groups according whether or not improvement of seizure control after surgery. Data collected for each child included: epileptic syndrome, etiology, age at epilepsy onset, duration of epilepsy and seizure frequency. Results. Comparison using a MANOVA test revealed significant differences across pre-operative Full Scale, Verbal Scale and Performance Scale (p = 0.01) with seizure reduction group performing better than no seizure reduction group. Seizureimprovement group achieved significant Performance Scale improvement (p = 0.01) and no seizure improvement groupshowed significant Verbal Scale worsened after surgery (p = 0.01).Conclusions. Our results suggest that the success of the epilepsy surgery in childhood when the seizure control is achieved may also provide an improvement in the Performance Scale whereas the seizure maintenance may worsen the Verbal Scale (AU)

Extratemporal damage in temporal lobe epilepsy: magnetization transfer adds information to volumetric MR imaging.

BACKGROUND AND PURPOSE: MTS is characterized by gliosis and atrophy of the hippocampus and related limbic structures. However, the damage is not limited to those structures with atrophy and has been reported in extratemporal regions. Because volumetric studies are nonspecific, the pathophysiology of the brain damage remains to be solved. MTI is an MR imaging technique more sensitive to subtle neuropathologic changes than conventional MR imaging. Here we combined MTI with VBM analysis to evaluate extratemporal damage in patients with TLE. MATERIALS AND METHODS: We studied 23 healthy controls and 21 patients with TLE with mean ages, respectively, of 37.6 ± 10.9 and 38.6 ± 9.02 years. All subjects had a full clinical follow-up and MR imaging. We processed the images with VBM for volumetric analysis of WM and GM, as well as with voxel-based analysis of MTR for macromolecular integrity analysis. RESULTS: In addition to MTR decrease in the temporal lobes, we found a significant decrease in GM and WM volumes. In the WM, the MTR decrease was correlated to volume loss detected by VBM, indicating that brain atrophy may explain part of the MTR decrease. We also found areas in which the MTR decrease was not associated with volume loss, suggesting an additional pathophysiologic process other than neuronal loss and atrophy underlying the MTR changes. CONCLUSIONS: Our results support the hypothesis that there are widespread lesions in the brain, including the corpus callosum and the frontal lobe, affecting both GM and WM.

When your child with epilepsy die suddenly: febrile seizures are part of the process? / Quando seu filho com epilepsia morre subitamente: crises febris fazem parte do processo?

Febrile seizures (FS) affect almost 2-5 percent of children and factors related to an increase susceptibility of children to FS may involve an imbalance of inflammatory cytokines and genetic factors. FS had low morbidity, but may be associated with the occurrence of late chronic epilepsy. Here we describe factors related to FS and its possible correlation with SUDEP.

Crises febris (CF) afetam aproximadamente 2-5 por cento das crianças e os fatores envolvidos com essa maior susceptibilidade das crianças às CF podem estar relacionados com uma ação inadequada de citocinas inflamatórias, além de fatores genéticos. As CF têm baixa morbidade, mas podem estar associadas à ocorrência de epilepsia crônica. Nós discutiremos os fatores relacionados com CF, considerando-se sua possível associação com SUDEP.

Medical image registration using TSallis Entropy in Statistical Parametric Mapping (SPM).

The superposition of medical images, technically known as co-registration, can take a major role in determining the topographic and morphological changes in functional diagnostic and therapeutic purposes. This paper describes a study focused on to find an alternative cost function method for medical images co-registration through the study of performance and robustness of the TSallis Entropy in Statistical Parametric Mapping package (SPM). Images of Magnetic Resonance (MR) and Single Photon Emission Computed Tomography (SPECT) of 3 patients morphologically normal were used for the construction of anatomic phantoms containing predetermined geometric variations. The simulated images were co-registered with the original images using traditional techniques and the proposed method. The comparative analysis of the Root Mean Square (RMS) error showed that the Tsallis Entropy was more efficient in the intramodality alignment, while the Shannon Entropy in the intermodality one; revealing therefore the importance of the implementation of the Tsallis Entropy in SPM for applications in neurology and neuropsychiatric evaluation.

A false case of clozapine-resistant schizophrenia.

One of the subjects that most concerns physicians is treatment-resistance. About 30%-60% of schizophrenia patients do not respond adequately to antipsychotic treatment and are known as refractory schizophrenia patients. Clozapine has been the drug of choice in such cases. However, approximately 30% of them do not respond to clozapine either. Here, we describe a patient with an initial diagnosis of refractory schizophrenia who had a history of dramatic aggressiveness. However, in this case, "refractoriness" was a wrong diagnosis. A case of psychosis secondary to epilepsy had been treated as schizophrenia for almost 20 years. Reports like this one are important because they remind us of how a thorough investigation can lead to the correct diagnosis and improve the patient's prognosis.

Calcified cysticercotic lesions and intractable epilepsy: a cross sectional study of 512 patients.

BACKGROUND: Neurocysticercosis is a major cause of epilepsy in developing countries and is endemic in Brazil. To test the hypothesis that the aetiological profile of patients with intractable epilepsy in Brazil includes neurocysticercosis, we conducted a cross sectional study investigating the aetiology of intractable epilepsy. METHODS: A total of 512 patients evaluated at the outpatient clinic for intractable epilepsy at the Ribeirão Preto School of Medicine were included in the survey. Medical intractability was determined on the basis of seizure incidence and severity, and response to appropriate epilepsy management. Neuroimaging included brain CT with non-contrasted and contrasted phases and high resolution MRI. Patients were divided into neurocysticercosis and non-neurocysticercosis groups according to previous diagnostic criteria. RESULTS: The most common epileptogenic lesions were mesial temporal sclerosis (MTS; 56.0%), malformations of cortical development (12.1%), and brain tumours (9.9%). Neuroimaging was normal in 8.7% of patients. Calcifications were found in 27% of patients and were significantly more common in patients with MTS than in those without MTS (p<0.001). Isolated neurocysticercosis was found in only eight patients (1.56%). CONCLUSIONS: These data suggest that neurocysticercosis is an uncommon cause of intractable epilepsy, even in an endemic region such as Brazil, and that it may only represent a coexistent pathology. However, an analysis of our findings reveals that neurocysticercosis was more common in patients with MTS. This finding could suggest either that there is a cause-effect relationship between MTS and neurocysticercosis, or that MTS and neurocysticercosis co-vary with a missing variable, such as socio-economic status.

Neuroethology application for the study of human temporal lobe epilepsy: from basic to applied sciences.

The aim of this investigation was to apply neuroethology to the study of human temporal lobe epilepsy (TLE). For this purpose, 42 seizures in 7 patients recorded during video/EEG monitoring (1997-1998) were analyzed by means of a behavioral glossary containing all behaviors. Video recordings were reobserved, and all patients' behaviors were annotated second-by-second. Data were analyzed using Ethomatic software and displayed as flowcharts including frequency, mean duration, and sequential statistic interaction of behavioral items (chi2 > or = 10.827, P<0.001). Flowcharts of (1) a group of seizures from a single patient, (2) the sum of four seizures per patient of two patients with right and five patients with left TLE, and (3) the comparison of left versus right TLE are shown. Well-established data in the literature were confirmed, such as aura (especially epigastric), contralateral lateralization value of dystonia and version, consciousness and language alterations in ictal and postictal periods, mostly with respect to dominant hemisphere involvement, among others. Less well established data such as awakening seizures in TLE patients, lateralization value of facial wiping (ipsilateral to the focus), statistically significant associations between behavioral pairs (dyads), and new behavioral sequences in TLE were also observed. We suggest that neuroethology also has great potential in the study of human epilepsy semiology. This work had an important role in method standardization for human epilepsy, setting the basis for the development of future clinical studies including correlation with other diagnostic methods (EEG, magnetic resonance, and SPECT). The next step will be the comparative study of seizures of patients with left and right TLE, with a greater number of patients, and the development of a digital video library.

Topiramate for the treatment of juvenile myoclonic epilepsy

OBJECTIVE: The aim of this study was to evaluate the efficacy and tolerability of topiramate (TPM) in juvenile myoclonic epilepsy (JME). METHOD: We assessed seizure control and adverse effects of TPM in 22 patients (18 females) aged 13 to 53 years. Target TPM dosage was up to 200 mg/day. The patients were subdivided into 3 groups: those treated with seizure control plus side effects (n=4); treated with non-controlled seizures (n=15) and with JME newly diagnosed (n=3). RESULTS: Sixteen patients completed the first year of the follow-up. Generalized tonic-clonic seizures were completely controlled in 10 (62.5%); more than 50% of reduction in 4 (25.0%) and less than 50% in 2 (12.5%). Myoclonia were controlled in 11 (68.8%) and persisted in 5 (31.2%) patients. Absence seizures were present in 5 (22.7%) of whom 2 (9.0%) showed more than 50% of seizure reduction while 3 (13.6%) presented worsening. Discontinuations were due to inadequate seizure control and adverse events (N=4), low compliance and loss of follow-up (N=2) and subject choice (N=1). CONCLUSION: TPM showed to be an effective and well-tolerated drug in the treatment of JME. Although frequently observed, TPM side effects were tolerable and the drug could be maintained in the majority of patients.

OBJETIVO: Avaliar a eficácia e tolerabilidade do topiramato (TPM) na epilepsia mioclônica juvenil (EMJ). MÉTODO: Avaliamos a resposta terapêutica e efeitos colaterais do TPM em 22 pacientes (18 mulheres) com idades entre 13 e 53 anos. A dose alvo utilizada foi até 200 mg/dia. Os pacientes foram divididos em 3 grupos no início do tratamento: aqueles com controle das crises mas que apresentavam efeitos colaterais (n=4); com crises não controladas (n=15) e com EMJ recém diagnosticada (n=3). RESULTADOS: Dezesseis pacientes completaram o primeiro ano de acompanhamento. Crises tônico-clonicas generalizadas foram completamente controladas em 10 (62,5%), tiveram redução maior de 50% em 4 (25,0%) e menor de 50% em 2 (12,5%). Mioclonias foram controladas em 11 (68,8%) e persistiram em 5 (31.2%) pacientes. As crises de ausências, presentes em 5 (22,7%) pacientes, tiveram redução maior do que 50% em 2 (9,0%) e agravamento em 3 (13,6%). A retirada do estudo foi devida principalmente ao controle inadequado das crises e efeitos colaterais indesejáveis (n=4), pouca adesão e perda do seguimento (n=2) e escolha do paciente (n=1). CONCLUSÃO: TPM foi considerada droga eficaz e bem tolerada no tratamento da EMJ. Apesar de freqüentemente observados, os efeitos colaterais do TPM foram toleráveis e a medicação pode ser mantida na maioria dos pacientes.

Suppression of obsessive-compulsive symptoms after epilepsy surgery.

We report two male patients with medically intractable epilepsy and obsessive-compulsive disorder (OCD) symptoms. Both patients experienced remission of obsessive-compulsive symptoms after surgical treatment of epilepsy. Although the surgeries targeted different brain regions, the two patients had in common unilateral anterior cingulate cortex ablation. On the basis of these observations, we discuss the pathophysiology of OCD symptoms, emphasizing the role of corticosubcortical pathways in their genesis. Our data suggest that surgeries that affect neural loops associated with obsessive-compulsive symptoms can lead to an improvement of OCD; however, the structures responsible for this effect cannot be conclusively determined.

Cognitive performance of patients with mesial temporal lobe epilepsy and incidental calcified neurocysticercosis.

OBJECTIVES: Although chronic calcified neurocysticercosis (NCC) has been considered a major cause of symptomatic epilepsy in developing countries, it can also be an incidental pathological finding in epileptic patients from endemic regions. The mechanisms of brain plasticity occurring in patients with NCC during and after the inflammatory process related to the parasite infection, death, degeneration, and calcification within the host brain might be an independent factor for cognitive impairment in patients with NCC and epilepsy. In order to assess this possibility cognitive performance of patients with mesial temporal lobe epilepsy related to hippocampal sclerosis (MTLE-HS) with and without NCC was investigated through structured neuropsychological testing. METHODS: Cognitive performance of long term MTLE-HS patients with (HS-NCC group, n = 32) and without NCC (HS only, n = 48) was compared. Imbalances between the two groups with respect to clinical, demographic, neuroimaging, and electrophysiological variables were adjusted by linear multiple regression analysis and Bonferroni correction for multiple tests. RESULTS AND CONCLUSIONS: There were no cognitive performance differences between HS-NCC and HS only patients, leading to the conclusion that chronic calcified NCC per se does not aggravate the cognitive performance of patients with long term MTLE-HS.

Cortical malformations are associated with a rare polymorphism of cellular prion protein.

Studies in animals lacking the cellular prion protein (PrP(c)) gene (Prnp) showed higher neuronal excitability in vitro and increased sensitivity to seizures in vivo. The authors previously reported a rare polymorphism at codon 171 (Asn-->Ser) of human Prnp to be associated with mesial temporal lobe epilepsy related to hippocampal sclerosis. They demonstrated that the same variant allele is also associated with symptomatic epilepsies related to different forms of malformations of cortical development.

Surgical outcome in mesial temporal sclerosis correlates with prion protein gene variant.

BACKGROUND: Mesial temporal lobe epilepsy related to hippocampal sclerosis (MTLE-HS) is the most common surgically remediable epileptic syndrome. Ablation of the cellular prion protein (PrP(c)) gene (PRNP) enhances neuronal excitability of the hippocampus in vitro and sensitivity to seizure in vivo, indicating that PrP(c) might be related to epilepsy. OBJECTIVE: To evaluate the genetic contribution of PRNP to MTLE-HS. METHODS: The PRNP coding sequence of DNA from peripheral blood cells of 100 consecutive patients with surgically treated MTLE-HS was compared to that from a group of healthy controls adjusted for sex, age, and ethnicity (n = 180). The presence of PRNP variant alleles was correlated with clinical and presurgical parameters as well as surgical outcome. RESULTS: A variant allele at position 171 (Asn-->Ser), absent in controls, was found in heterozygosis (Asn171Ser) in 23% of patients (p < 0.0001). The PRNP genotypes were not correlated with any clinical or presurgical data investigated. However, patients carrying the Asn171Ser variant had a five times higher chance of continuing to have seizures after temporal lobectomy (95% CI 1.65 to 17.33, p = 0.005) than those carrying the normal allele. At 18 months after surgery, 91.8% of patients with the normal allele at codon 171 were seizure free, in comparison to 68.2% of those carrying Asn171Ser (p = 0.005). CONCLUSIONS: The PRNP variant allele Asn171Ser is highly prevalent in patients with medically untreatable MTLE-HS and influences their surgical outcome. The results suggest that the PRNP variant allele at codon 171 (Asn171Ser) is associated with epileptogenesis in MTLE-HS.

Accuracy of ictal SPECT in mesial temporal lobe epilepsy with bilateral interictal spikes.

OBJECTIVE: In mesial temporal lobe epilepsy (MTLE), the rate of correct seizure lateralization of ictal semiology and ictal EEG is better for patients with unilateral interictal spikes (UIS) than for patients with bilateral interictal spikes (BIS), possibly due to rapid seizure propagation patterns associated with bilateral epileptogenesis. In this study, the authors investigated if ictal SPECT is a reliable diagnostic test for both UIS and BIS patients. METHODS: Video-EEG recording was used as the gold standard to examine the accuracy of ictal SPECT and its relationship with interictal and ictal EEG. Ninety-three consecutive patients with MTLE associated with hippocampal sclerosis were included in the analysis. Ictal SPECT was considered accurate if two blinded observers independently lateralized the scan correctly. RESULTS: Ictal SPECT correctly lateralized 75 (80.6%) of 93 scans. The rate of correct seizure lateralization was 87.6% for the UIS group and only 55.0% for the BIS group (p = 0.0027). In the EEG epochs, 66.7% of BIS patients vs 43.4% of UIS patients had nonlateralized ictal EEG (p < 0.001). CONCLUSION: The authors conclude that the accuracy of ictal SPECT is worse for MTLE patients with BIS than for those with UIS. The role of ictal SPECT in presurgical evaluation of patients with BIS must be reviewed.

Serial EEG during human status epilepticus: evidence for PLED as an ictal pattern.

OBJECTIVE: To analyze the relationship between periodic lateralized epileptiform discharges (PLED) and status epilepticus (SE), to evaluate the relationship between mortality and periodic patterns, and to determine whether a stereotypic sequence of EEG patterns exists during human SE. METHODS: The authors performed a prospective clinical and electrographic study comprising 62 episodes of SE, 55 patients, and 254 ictal/postictal EEG recordings. Serial daily EEG were obtained in all cases. RESULTS: Partial SE was the predominant clinical type. Four distinct ictal EEG patterns were identified: intermittent EEG seizures (IES), merging EEG seizures (MES), continuous ictal discharges (CID), and periodic epileptiform discharges (PED) which could be lateralized (PLED) or bilateral (PBED). IES was the most common ictal pattern. In the same record, only one combination of ictal patterns was observed corresponding to an association of PLED or PBED and MES pattern. Serial EEG demonstrated that approximately one-third of SE resolved before the second EEG, another one-third persisted and maintained the same ictal pattern throughout the entire evolution, and the final one-third showed variable ictal EEG patterns. PLED were also unequivocally associated with epileptic seizures, and in some patients were the initial ictal pattern. CONCLUSION: PLED can be an ictal pattern; and, in contrast to previous observations, no stereotyped sequence of ictal EEG patterns was found. PLED/PBED were not a terminal ictal pattern in every case, and outcome was more related to age and etiology than to specific ictal EEG patterns.

Typical and atypical perfusion patterns in periictal SPECT of patients with unilateral temporal lobe epilepsy.

PURPOSE: To characterize perfusion patterns of periictal single-photon emission tomography (SPECT) in patients with unilateral temporal lobe epilepsy (TLE) and to determine their relationship to the epileptogenic zone (EZ). METHODS: We studied periictal SPECT scans of 53 patients after anterior mesial temporal lobectomy who had good seizure outcome after surgery. Ictal SPECT scans were performed during video-EEG monitoring. Typical SPECT patterns consisted of ipsilateral ictal hyperperfusion or ipsilateral postictal hypoperfusion. Atypical ictal patterns included normal scans, bilateral temporal hyperperfusion, or contralateral patterns. These perfusion patterns were retrospectively analyzed searching for concordance rate with the EZ. RESULTS: We obtained 51 ictal and two early postictal scans. In the typical group, 40 (75.4%) patients had ipsilateral ictal temporal lobe hyperperfusion, and one (1.9%) patient had ipsilateral postictal temporal lobe hypoperfusion. Twelve (22.7%) patients exhibited atypical perfusion patterns: seven (13.2%) patients had bitemporal ictal hyperperfusion (four cases showed asymmetric temporal lobe changes), four (7.6%) patients had contralateral hyperperfusion, and one (1.9%) patient had a normal SPECT scan. All four patients with bitemporal asymmetric hyperperfusions showed greater perfusion lateralized to the side of the EZ. Three of the four patients who had contralateral hyperperfusion also had a complex postictal-like pattern in the ipsilateral temporal lobe consisting of anteromesial hyperperfusion with adjacent lateral hypoperfusion. CONCLUSIONS: This study analyzed typical and atypical perfusion patterns in unilateral TLE, and suggested that not only typical, but also some atypical perfusion patterns may contribute to the lateralization of EZ.

Calcified neurocysticercotic lesions and postsurgery seizure control in temporal lobe epilepsy.

BACKGROUND: Several studies suggest that neurocysticercosis is the main cause of symptomatic epilepsy in developing countries. In such areas, calcified cysticercotic lesions (CCL) are frequently found in patients with complex partial seizures associated with hippocampal sclerosis (HS). The authors studied whether there are clinical and pathologic differences between HS patients with and without CCL. METHODS: The authors determined the clinical and pathologic findings of 30 patients with HS and compared them with 32 patients with HS + CCL. Hippocampi from both groups were measured for fascia dentata Timm staining and cell density in hippocampal subfields. RESULTS: In the HS + CCL group, single or multiple CCL were found in all lobes with no lobar predominance. An initial precipitating event occurred in 83.3% of HS and in 62.5% of HS + CCL. First complex partial seizure occurred at 10.1 years in HS and at 11.9 years in HS + CCL. No significant differences were found for fascia dentata Timm staining and hippocampal cell densities. Good postsurgery outcome (Engel I classification) did not differ between groups, with this result occurring in 76.6% of patients with HS and 81.2% of patients with HS + CCL. CONCLUSIONS: The presence of CCL does not influence the clinical and pathologic profile of patients with hippocampal atrophy. Clinical histories and postsurgical outcomes were similar to those of patients with classic HS, suggesting that the CCL is probably, in this set of patients, a coincidental pathology and does not have a role in epileptogenesis.

Hippocampal GABA and glutamate transporter immunoreactivity in patients with temporal lobe epilepsy.

OBJECTIVE: Sodium-coupled transporters remove extracellular neurotransmitters and alterations in their function could enhance or suppress synaptic transmission and seizures. This study determined hippocampal gamma-aminobutyric acid (GABA) and glutamate transporter immunoreactivity (IR) in temporal lobe epilepsy (TLE) patients. METHODS: Hippocampal sclerosis (HS) patients (n = 25) and non-HS cases (mass lesion and cryptogenic; n = 20) were compared with nonseizure autopsies (n = 8). Hippocampal sections were studied for neuron densities along with IR for glutamate decarboxylase (GAD; presynaptic GABA terminals), GABA transporter-1 (GAT-1; presynaptic GABA transporter), GAT-3 (astrocytic GABA transporter), excitatory amino acid transporter 3 (EAAT3; postsynaptic glutamate transporter), and EAAT2-1 (glial glutamate transporters). RESULTS: Compared with autopsies, non-HS cases with similar neuron counts showed: 1) increased GAD IR gray values (GV) in the fascia dentata outer molecular layer (OML), hilus, and stratum radiatum; 2) increased GAT-1 OML GVs; 3) increased astrocytic GAT-3 GVs in the hilus and Ammon's horn; and 4) no IR differences for EAAT3-1. HS patients with decreased neuron densities demonstrated: 1) increased OML and inner molecular layer GAD puncta; 2) decreased GAT-1 puncta relative to GAD in the stratum granulosum and pyramidale; 3) increased GAT-1 OML GVs; 4) decreased GAT-3 GVs; 5) increased EAAT3 IR on remaining granule cells and pyramids; 6) decreased glial EAAT2 GVs in the hilus and CA1 stratum radiatum associated with neuron loss; and 7) increased glial EAAT1 GVs in CA2/3 stratum radiatum. CONCLUSIONS: Hippocampal GABA and glutamate transporter IR differ in TLE patients compared with autopsies. These data support the hypothesis that excitatory and inhibitory neurotransmission and seizure susceptibility could be altered by neuronal and glial transporters in TLE patients.

Altered hippocampal kainate-receptor mRNA levels in temporal lobe epilepsy patients.

This study determined whether hippocampal kainate (KA) receptor mRNA levels were increased or decreased in temporal lobe epilepsy patients compared with nonseizure autopsies. Hippocampal sclerosis (HS; n = 17), nonsclerosis (non-HS; n = 11), and autopsy hippocampi (n = 9) were studied for KA1-2 and GluR5-7 mRNA levels using semiquantitative in situ hybridization techniques, along with neuron densities. Compared with autopsy hippocampi, HS and non-HS cases showed decreased GluR5 and GluR6 hybridization densities per CA2 and/or CA3 pyramid. Furthermore, HS patients demonstrated increased KA2 and GluR5 hybridization densities per granule cell compared with autopsy hippocampi. These findings indicate that chronic temporal lobe seizures were associated with differential changes in hippocampal KA1-2 and GluR5-7 hybridization densities that vary by subfield and pathology group. In temporal lobe epilepsy patients, these results support the hypothesis that pyramidal cell GluR5 and GluR6 mRNA levels are decreased as a consequence of seizures, and in HS patients granule cell KA2 and GluR5 mRNA levels are increased in association with aberrant fascia dentata mossy fiber sprouting and/or hippocampal neuronal loss.

Increased hippocampal AMPA and NMDA receptor subunit immunoreactivity in temporal lobe epilepsy patients.

This study determined if hippocampal AMPA and NMDA subunit immunoreactivity (IR) in temporal lobe epilepsy patients was increased compared with nonseizure autopsies. Hippocampi from hippocampal sclerosis patients (HS; n = 26) and nonsclerosis cases (non-HS: n = 12) were compared with autopsies (n = 6) and studied for GluR1, GluR2/3, NMDAR1, and NMDAR2 IR gray values (GV) along with fascia dentata and Ammon's horn neuron densities. Compared with autopsies, non-HS cases with similar neuron densities and HS patients with decreased neuron densities showed: (a) Increased GluR1 GVs in the fascia dentata molecular layer: (b) increased NMDAR1 GVs in the CA3-1 stratum radiatum and greater IR within pyramids; and (c) increased GluR2/3 and NMDAR2 GVs throughout all hippocampal subfields. Furthermore, HS patients showed that relative to the outer molecular layer: (a) GluR1 GV differences were decreased in the CA4/hilar region and CA1 stratum radiatum compared with autopsies; and (b) NMDAR2 GV differences were increased in the inner molecular layer compared with non-HS cases. In temporal lobe seizure patients, these results indicate that AMPA and NMDA receptor subunit IR was increased in HS and non-HS hippocampi compared with nonseizure autopsies. In humans, these findings support the hypothesis that glutamate receptor subunits are increased in association with chronic temporal lobe seizures, which may enhance excitatory neurotransmission and seizure susceptibility.