Surgical Outcome in Extratemporal Epilepsies Based on Multimodal Pre-Surgical Evaluation and Sequential Intraoperative Electrocorticography.

OBJECTIVE: to present the postsurgical outcome of extratemporal epilepsy (ExTLE) patients submitted to preoperative multimodal evaluation and intraoperative sequential electrocorticography (ECoG). SUBJECTS AND METHODS: thirty-four pharmaco-resistant patients with lesional and non-lesional ExTLE underwent comprehensive pre-surgical evaluation including multimodal neuroimaging such as ictal and interictal perfusion single photon emission computed tomography (SPECT) scans, subtraction of ictal and interictal SPECT co-registered with magnetic resonance imaging (SISCOM) and electroencephalography (EEG) source imaging (ESI) of ictal epileptic activity. Surgical procedures were tailored by sequential intraoperative ECoG, and absolute spike frequency (ASF) was calculated in the pre- and post-resection ECoG. Postoperative clinical outcome assessment for each patient was carried out one year after surgery using Engel scores. RESULTS: frontal and occipital resection were the most common surgical techniques applied. In addition, surgical resection encroaching upon eloquent cortex was accomplished in 41% of the ExTLE patients. Pre-surgical magnetic resonance imaging (MRI) did not indicate a distinct lesion in 47% of the cases. In the latter number of subjects, SISCOM and ESI of ictal epileptic activity made it possible to estimate the epileptogenic zone. After one- year follow up, 55.8% of the patients was categorized as Engel class I-II. In this study, there was no difference in the clinical outcome between lesional and non lesional ExTLE patients. About 43.7% of patients without lesion were also seizure- free, p = 0.15 (Fischer exact test). Patients with satisfactory seizure outcome showed lower absolute spike frequency in the pre-resection intraoperative ECoG than those with unsatisfactory seizure outcome, (Mann- Whitney U test, p = 0.005). CONCLUSIONS: this study has shown that multimodal pre-surgical evaluation based, particularly, on data from SISCOM and ESI alongside sequential intraoperative ECoG, allow seizure control to be achieved in patients with pharmacoresistant ExTLE epilepsy.

New Aspects of VEGF, GABA, and Glutamate Signaling in the Neocortex of Human Temporal Lobe Pharmacoresistant Epilepsy Revealed by RT-qPCR Arrays.

In the epilepsy spectrum, temporal lobe epilepsy (TLE) is the most common and devastating focal and symptomatic epilepsy form in adults, where more than 30% of patients develop pharmacoresistance. It is not fully understood how the gene expression contributes to establishing an epileptic phenotype. Cerebrovascular remodeling directed by VEGF (vascular endothelial growth factor) signaling might modulate the synaptic neurotransmission in the epileptic brain. To address this question, the gene expression was profiled in biopsies of the temporal cortex from diagnosed patients with pharmacoresistant TLE that underwent surgical resection to seizure control. One hundred sixty-eight genes related to VEGF signaling and GABA and glutamate neurotransmissions were evaluated. Genes related to downstream signaling -phosphoinositide 3-kinase (PI3K), mitogen-activated protein kinases (MAPK), and Janus-activated kinase/signal transducer and activator of transcription (JAK/STAT) pathways- and neurotransmitters metabolism were evaluated too. Thirty-nine genes were upregulated. The genes encoding for G protein q polypeptide, serine racemase, gephyrin, and glutamate/cystine antiporter system xCT appeared as novel upregulated genes in the pharmacoresistant TLE. ClueGO, a Cytoscape plugin, was used to build a gene network associated using Gene Ontology (GO) terminology. Enrichment analysis by ClueGO retrieves that positive regulation of endothelial cell proliferation, nerve development, and neuronal apoptosis were over-represented categories. In conclusion, VEGF signaling is confirmed as a relevant mediator in the pharmacoresistant TLE. In addition, the enrichment analysis applied to differentially expressed genes suggests new pharmacological targets to be assessed in the treatment of pharmacoresistant TLE. Results make up an approximation to better understand the epileptic brain and complement the available data.

Motor Coordination Disorders Evaluated through the Grid Test and Changes in the Nigral Nrf2 mRNA Expression in Rats with Pedunculopontine Lesion.

Neurotoxic lesion of the pedunculopontine nucleus (PPN) is known to cause subtle motor dysfunctions. However, motor coordination during advance on a discontinuous and elevated surface has not been studied. It is also not known whether there are changes in the mRNA expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in nigral tissue. METHODS: The effects of the unilateral neurotoxic lesion of the PPN in motor coordination evaluated through grid test and Nrf2 mRNA expression in nigral tissue were evaluated. Two experimental designs (ED) were organized: ED#1 behavioral study (7 and 30 days after PPN lesion) and ED#2 molecular biology study (24 h, 48 h and 7 days) after PPN lesion. RESULTS: ED#1-The number of faults made with left limbs, were significant higher in the lesioned groups (p < 0.01) both 7 and 30 days post-lesion. The number of failures made by the right limbs, was also significantly higher (p < 0.05) vs. control groups. ED#2-Nrf2 mRNA expression showed an increase 24 h after PPN injury (p < 0.01), followed by a peak of expression 48 h post injury (p < 0.001). CONCLUSIONS: Disorders of motor coordination associated with PPN injury are bilateral. The increased Nrf2 mRNA expression could represent an adaptive response to oxidative stress in the nigral tissue following pontine injury.

Tyrosine Hydroxylase, Vesicular Monoamine Transporter and Dopamine Transporter mRNA Expression in Nigrostriatal Tissue of Rats with Pedunculopontine Neurotoxic Lesion.

BACKGROUND: The degeneration of the pedunculopontine nucleus (PPN) precedes the degeneration of the nigral cells in the pre-symptomatic stages of Parkinson's disease (PD). Although the literature recognizes that a lesion of the PPN increases the vulnerability of dopaminergic cells, it is unknown if this risk is associated with the loss of capability of handling the dopaminergic function. METHODS: In this paper, the effects of a unilateral neurotoxic lesion of the PPN in tyrosine hydroxylase (TH), vesicular monoamine transporter 2 (VMAT2) and dopamine transporter (DAT) mRNA expression in nigrostriatal tissue were evaluated. Three experimental groups were organized: non-treated rats, NMDA-lesioned rats and Sham-operated rats. RESULTS: Seven days after the PPN lesion, in nigral tissue, TH mRNA expression was higher in comparison with control groups (p < 0.05); in contrast, VMAT2 mRNA expression showed a significant decrease (p < 0.01). DAT mRNA expression showed a significant decrease (p < 0.001) in the striatal tissue. Comparing nigral neuronal density of injured and control rats revealed no significant difference seven days post-PPN injury. CONCLUSIONS: Findings suggest that the PPN lesion modifies the mRNA expression of the proteins associated with dopaminergic homeostasis at nigrostriatal level. It could represent vulnerability signals for nigral dopaminergic cells and further increase the risk of degeneration of these cells.

Follow-Up of Peripheral IL-1ß and IL-6 and Relation with Apoptotic Death in Drug-Resistant Temporal Lobe Epilepsy Patients Submitted to Surgery.

Increasing amounts of evidence support the role of inflammation in epilepsy. This study was done to evaluate serum follow-up of IL-1ß and IL-6 levels, as well as their concentration in the neocortex, and the relationship of central inflammation with NF-κB and annexin V in drug-resistant temporal lobe epileptic (DRTLE) patients submitted to surgical treatment. Peripheral and central levels of IL-1ß and IL-6were measured by ELISA in 10 DRTLE patients. The sera from patients were taken before surgery, and 12 and 24 months after surgical treatment. The neocortical expression of NF-κB was evaluated by western blotting and annexin V co-localization with synaptophysin by immunohistochemistry. The neocortical tissues from five patients who died by non-neurological causes were used as control. Decreased serum levels of IL-1 and IL-6 were observed after surgery; at this time, 70% of patients were seizure-free. No values of IL-1 and IL-6 were detected in neocortical control tissue, whereas cytokine levels were evidenced in DRTLE. Increased NF-κB neocortex expression was found and the positive annexin V neurons were more obvious in the DRTLE tissue, correlating with IL-6 levels. The follow-up study confirmed that the inflammatory alterations disappeared one year after surgery, when the majority of patients were seizure-free, and the apoptotic death process correlated with inflammation.

Oxidative Stress in Patients with Drug Resistant Partial Complex Seizure.

Oxidative stress (OS) has been implicated as a pathophysiological mechanism of drug-resistant epilepsy, but little is known about the relationship between OS markers and clinical parameters, such as the number of drugs, age onset of seizure and frequency of seizures per month. The current study’s aim was to evaluate several oxidative stress markers and antioxidants in 18 drug-resistant partial complex seizure (DRPCS) patients compared to a control group (age and sex matched), and the results were related to clinical variables. We examined malondialdehyde (MDA), advanced oxidation protein products (AOPP), advanced glycation end products (AGEs), nitric oxide (NO), uric acid, superoxide dismutase (SOD), glutathione, vitamin C, 4-hydroxy-2-nonenal (4-HNE) and nitrotyrosine (3-NT). All markers except 4-HNE and 3-NT were studied by spectrophotometry. The expressions of 4-HNE and 3-NT were evaluated by Western blot analysis. MDA levels in patients were significantly increased (p ≤ 0.0001) while AOPP levels were similar to the control group. AGEs, NO and uric acid concentrations were significantly decreased (p ≤ 0.004, p ≤ 0.005, p ≤ 0.0001, respectively). Expressions of 3-NT and 4-HNE were increased (p ≤ 0.005) similarly to SOD activity (p = 0.0001), whereas vitamin C was considerably diminished (p = 0.0001). Glutathione levels were similar to the control group. There was a positive correlation between NO and MDA with the number of drugs. The expression of 3-NT was positively related with the frequency of seizures per month. There was a negative relationship between MDA and age at onset of seizures, as well as vitamin C with seizure frequency/month. We detected an imbalance in the redox state in patients with DRCPS, supporting oxidative stress as a relevant mechanism in this pathology. Thus, it is apparent that some oxidant and antioxidant parameters are closely linked with clinical variables.

Long-Term Electroclinical and Employment Follow up in Temporal Lobe Epilepsy Surgery. A Cuban Comprehensive Epilepsy Surgery Program.

The purpose of this paper is to present a long- term electroclinical and employment follow up in temporal lobe epilepsy (TLE) patients in a comprehensive epilepsy surgery program. Forty adult patients with pharmacoresistant TLE underwent detailed presurgical evaluation. Electroencephalogram (EEG) and clinical follow up assessment for each patient were carried out. The occurrence of interictal epileptiform activity (IEA) and absolute spike frequency (ASF) were tabulated before and after 1, 6, 12, 24 and 72 months surgical treatment. Employment status pre- to post-surgery at the last evaluated period was also examined. Engel scores follow-up was described as follows: at 12 months 70% (28) class I, 10% (4) class II and 19% (8) class III-IV; at 24 months after surgery 55.2% (21) of the patients were class I, 28.9% (11) class II and 15.1% (6) class III-IV. After one- year follow up 23 (57.7%) patients were seizure and aura-free (Engel class IA). These figures changed to 47.3%, and 48.6% respectively two and five years following surgery whereas 50% maintained this condition in the last follow up period. A decline in the ASF was observed from the first year until the sixth year after surgery in relation to the preoperative EEG. The ASF one year after surgery allowed to distinguish "satisfactory" from "unsatisfactory" seizure relief outcome at the last follow up. An adequate social functioning in terms of education and employment in more than 50% of the patients was also found. Results revealed the feasibility of conducting a successful epilepsy surgery program with favorable long term electroclinical and psychosocial functioning outcomes in a developing country as well.

Relation of Structural and Functional Changes in Auditory and Visual Pathways after Temporal Lobe Epilepsy Surgery.

Auditory and visual pathways may be affected as a consequence of temporal lobe epilepsy surgery because of their anatomical relationships with this structure. The purpose of this paper is to correlate the results of the auditory and visual evoked responses with the parameters of tractography of the visual pathway, and with the state of connectivity between respective thalamic nuclei and primary cortices in both systems after the surgical resection of the epileptogenic zone in drug-resistant epileptic patients. Tractography of visual pathway and anatomical connectivity of auditory and visual thalamus-cortical radiations were evaluated in a sample of eight patients. In general, there was a positive relationship of middle latency response (MLR) latency and length of resection, while a negative correlation was found between MLR latency and the anatomical connection strength and anatomical connection probability of the auditory radiations. In the visual pathway, significant differences between sides were found with respect to the number and length of tracts, which was lower in the operated one. Anatomical connectivity variables and perimetry (visual field defect index) were particularly correlated with the latency of P100 wave which was obtained by quadrant stimulation. These results demonstrate an indirect functional modification of the auditory pathway and a direct traumatic lesion of the visual pathway after anterior temporal lobectomy in patients with drug resistant epilepsy.

Motor dysfunction and alterations in glutathione concentration, cholinesterase activity, and BDNF expression in substantia nigra pars compacta in rats with pedunculopontine lesion.

Pedunculopontine nucleus (PPN) has been considered a critically important region in the regulation of some of the physiological functions that fail during the progression of Parkinson's disease (PD). In this paper, the effects of unilateral neurotoxic lesion of the PPN [through the injection of N-methyl-d-aspartate (NMDA) solution (concentration: 0.1M; volume: 0.5µL)] in motor execution and gait disorders and the changes in cellular and molecular indicators in rat nigral tissue were evaluated. The motor execution was assessed using the beam test (BT) and the gait disorders by footprint test. Glutathione (GSH) concentrations, acetyl cholinesterase enzymatic activity (AChE EA), and brain-derived neurotrophic factor (BDNF) mRNA expression in nigral tissue were analyzed. NMDA-lesioned rats showed fine motor dysfunction with a significant increase in the slow (p≤0.01) and fast movement (p≤0.01) time and in path deviation (p≤0.01) on the smaller diameter beams. Moreover, NMDA-lesioned rats exhibited an imprecise path with moments of advances and setbacks, alternating with left and right deviations, suspensions, and inverted positions. Footprint test revealed slight gait disorders, which were manifested by a reduction in the left and right stride lengths, the intra-step distance, and the support area (p≤0.01). Biochemical studies showed that 48h after the PPN neurotoxic injury, the GSH concentrations and BDNF expression were significantly increased (p≤0.01). These variables returned to normal values 7days after the PPN lesion; the AChE EA showed a significant increase at this time. These functional changes in nigral tissue could be a plastic responses associated with early PD.

Multimodal imaging in nonlesional medically intractable focal epilepsy.

Identification and localization of epileptogenic zone (EZ) is vital in patients with medically-intractable focal epilepsy, who may be candidates for potentially curative resective epilepsy surgery. Presence of a lesion on magnetic resonance imaging (MRI) influences both diagnostic classification and selection for surgery. However, the implications for MRI-negative cases are not well-defined for such patients. Most of these patients undergo invasive long-term Electroencephalography recordings before a final decision regarding resection is possible. Recent developments in structural and functional neuroimaging which include quali-quantitative MRI, Positron Emission Tomography, Single Photon Emission Computed Tomography, and functional MRI have significantly changed presurgical epilepsy evaluation. Source analysis based on electrophysiological information, using either EEG or magnetoencephalography are also promising in order to noninvasively localize the EZ and to guide surgery in medically-intractable focal epilepsy patients that exhibit nonlesional MRI. This chapter aims to review the value of the combined use of structural and functional imaging techniques, and how this multimodal approach improves both selection of surgical candidates and post-operative outcomes in medically-intractable nonlesional focal epilepsy.

Temporal lobe epilepsy surgery modulates the activity of auditory pathway.

The purpose of this paper is to evaluate the effects of the anterior temporal lobectomy on the functional state of the auditory pathway in a group of drug-resistant epileptic patients, linking the electrophysiological results to the resection magnitude. Twenty-seven patients with temporal lobe epilepsy and a matched control group were studied. Auditory brainstem and middle latency responses (ABR and MLR respectively) were carried out before and after 6, 12 and 24 months surgical treatment. The volume and longitude of temporo-mesial resected structures were estimated on magnetic resonance images taken 6 months after surgery. Before the intervention the patients showed a significant delay of latency in waves III, V, Pa and Nb, with an increase in duration of I-V interval in comparison with healthy subjects (Mann-Whitney U-test, p<0.05). After resection, additional significant differences in waves I and Na latency were observed. Na and Pa waveforms showed a tendency to increase in amplitude, which became statistically significant 12 months after surgery for right hemisphere lobectomized patients in the midline electrode, and in Pa waveform for all patients in the temporal electrodes ipsilateral to resection (Wilcoxon test, p<0.05). In general, latency variations of MLR correlated with resection longitude, while changes in amplitude correlated with the volume of the resection in the middle temporal pole and amygdala (Pearson' correlation test, p<0.05). As a result, we assume that anterior temporal lobectomy provokes functional modifications into the auditory pathway, probably related to an indirect modulation of its activity by the temporo-mesial removed structures.

Inflammatory mediators in epilepsy.

All common contributing factors to epilepsy such as trauma, malignancies and infections are accompanied by different levels of central nervous system inflammation that in turn have been associated with the occurrence of seizure. Emerging data from human brain tissue and experimental models of epilepsy support the proposed involvement of inflammation in epilepsy. Key mediators of this process include, among others: interleukin (IL) -1ß, IL-6, tumor necrosis factor-α, adhesion molecules and component of complement. Recent advances suggest the involvement of specific inflammatory pathways in the pathogenesis of seizures in patients with pharmacoresistant temporal lobe epilepsy, highlighting the potential for new therapeutic strategies. This review provides an overview of the current knowledge on the relationship between inflammatory mediators and epilepsy. We also describe experimental and clinical evidence of inflammation in epilepsy with special emphasis on clinical aspects once the epileptogenic focus has been resected. Further insight into the complex role of inflammation in epileptogenesis may provide new treatment options.

Resección microquirúrgica guiada de las malformaciones arteriovenosas cerebrales. Experiencia cubana y revisión / Guided resection microsurgery of cerebral arteriovenous malformations. Cuban experience and review

Objetivos: Se presenta un nuevo método para la resección de las malformaciones arteriovenosas (MAVs) usando una guía imagenológica transoperatoria con imágenes de angiografía por sustracción digital (ASD) combinada con imágenes de tomografía axial computada (TAC) y se describen nuestros primeros resultados quirúrgicos. Método: Se utilizan dos sistemas estereotácticos (Leksell y Estereoflex), softwre de planificación quirúrgicas (STASSIS y ANGIOWIN) y una unidad fluoroscópica portátil (SIREMOBIL 2000). Los pacientes se seleccionaron para el proceder quirúrgico después de realizar la gradación de la MAVs según Spetzler y Martín. La selección de la ADS como guía imagenológica transoperatoria se baso en la visualización bien definida de uno o más aferencias a la MAVs (pedículos). Los procederes microquirúrgicos se realizaron acorde a los métodos técnicos estándar en la resección de una MAVs, a los que se sumo la localización más ajustada de la craneotomía, la identificación rápida y precoz de las aferencias arteriales, así como la identificación precisa de los límites del nido malformativo. Resultados: En los 22 pacientes incluídos las formas clínicas más frecuentes de presentación de una MAVs fueron las hemorragias y/o convulsiones. La localización fue variable con predominio de las supratentoriales en regiones corticales. Según la clasificación de Spetzler y Martín, se incluyeron desde el grado I hasta el IV, con predominio en los grados I y III. La exérensis total se realizó en más del 90 por ciento de nuestros pacientes, utilizándose en el 100 por ciento la guía por imágenes y en el 45,5 por ciento de las intervenciones de la ADS transopeatoria postresección. La morbilidad neurológica permanente fue de solo el 4,5 por ciento y la mortalidad del 9,1 por ciento. Al año de evolución el 83,4 por ciento se consideraron pacientes con buenos resultados quirúrgicos. Conclusiones: La microcirugía se reafirma como modalidad de tratamiento efectiva. Esta combinación de métodos facilita la identificación, presillado y exéresis de los componentes de las MAVs, con un índice mínimo de complicaciones permanentes y aceptable mortalidad, considerando su clasificación.

Plasmocitoma solitario de cabeza y cuello: presentación de dos casos / Solitary plasmocitoma of head and neck

Se evaluaron los expedientes clínicos de dos pacientes atendidos en el Servicio de Cabeza y Cuello del Instituto Nacional de Oncología de la Habana, en los años 1997 y 1998, con sintomatología de obstrucción nasal de entre 8 meses y 1 año de evolución, detect ndose en ambos casos lesiones del maciso facial y cuyo diagnóstico fue: Plasmocitoma. El primer caso se trataba de una paciente del sexo femenino, de 48 años de edad, con una tumoración del seno maxilar derecho con destrucción de todas sus paredes y en la que fue necesario una maxilectomía derecha para concluir el diagnóstico. Durante el estudio posterior se encontró un tumor abdominal planific ndose una laparatomía exploradora que teniendo en cuenta los hallazgos transoperatorios, se realizó una histerectomía total con doble anexectomía cuyo resultado anatomopatológico fue: cistadenoma seroso; en la actualidad se encuentran completando su estudio. El segundo caso, se trataba de un paciente del sexo masculino de 54 años de edad, con una tumoración de la región medio facial al cual se le planificó tratamiento combinado con poliquimioterapia y radioterapia con Co60, encontr ndose actualmente controlado de su enfermedad. En ambos pacientes no se encontró presencia de lesión a otro nivel en examen físico y estudio radiogr fico, biopsia de m,dula ósea normal, función renal conservada, niveles de calcio y hemoglobina dentro de límites normales

Tumores intraventriculares supratentoriales primarios / Supratentorial intraventricular primary tumors

Introducción. Son raros los tumores con una localización intraventricular supratentorial primaria. Resulta de mayor frecuencia la extensión intraventricular, entre los tumores que se comportan de este modo est el astrocitoma del hipot lamo y del nervio óptico, linfomas, subependimomas, craneofaringionmas y carcinomas metastasicos. Pacientes y metodos. Se realizó un estudio restrospectivo con las historias clínicas de 11 pacientes ingresados en el CIREN en el período comprendido de enero de 1996 a noviembre de 1999 con diagnóstico clínico de tumor intraventricular supratentorial. De los 11 enfermos, 8 correspondieron al sexo masculino y 3 al femenino. La edad osciló entre 15 meses y 51 años. La afectación ventricular fue la siguiente: cinco tumores afectaron el ventrículo lateral y seis al tercer ventrículo. Los procederes diagnóstico terap,utico de los casos estudiados, resecados total o parcialmente fueron los siguientes, cinco abordajes transcalloso, cuatro abordajes transcortical, una resección neuroendoscópica y una biopsia estereotoxica. Una vez resecado el tejido se procesó histológicamente, a 4 de ellos se les realizó tecnicas inmunohistoquímicas y a 3 estudio por microscopía electrónica para confirmar el diagnóstico. Resultados. El an lisis histológico fue el siguiente: 3 pacientes con diagnóstico de neurocitoma central, 3 con quiste coloide, 1 astrocitoma pilocítico, 1 tumor neuroectod,rmico primitico, 1 ependimoma, 1 meningioma (transicional) y una lesión inflamatoria crónica de causa no precisada. Es objetivo del presente trabajo comunicar nuestra experiencia, así como confirmar que las lesiones localizadas en los ventrículos laterales y en el tercero son raras si tenemos en cuenta que se trataron 109 lesiones tumorales del sistema Nervioso en nuestro centro en el tiempo referido anteriormente