Morphological alterations of the neuronal Golgi apparatus upon seizures.

AIMS: Epilepsy is one of the most common chronic neurological disorders, affecting around 50 million people worldwide, but its underlying cellular and molecular events are not fully understood. The Golgi is a highly dynamic cellular organelle and can be fragmented into ministacks under both physiological and pathological conditions. This phenomenon has also been observed in several neurodegenerative disorders; however, the structure of the Golgi apparatus (GA) in human patients suffering from epilepsy has not been described so far. The aim of this study was to assess the changes in GA architecture in epilepsy. METHODS: Golgi visualisation with immunohistochemical staining in the neocortex of adult patients who underwent epilepsy surgery; 3D reconstruction and quantitative morphometric analysis of GA structure in the rat hippocampi upon kainic acid (KA) induced seizures, as well as in vitro studies with the use of Ca2+ chelator BAPTA-AM in primary hippocampal neurons upon activation were performed. RESULTS: We observed GA dispersion in neurons of the human neocortex of patients with epilepsy and hippocampal neurons in rats upon KA-induced seizures. The structural changes of GA were reversible, as GA morphology returned to normal within 24 h of KA treatment. KA-induced Golgi fragmentation observed in primary hippocampal neurons cultured in vitro was largely abolished by the addition of BAPTA-AM. CONCLUSIONS: In our study, we have shown for the first time that the neuronal GA is fragmented in the human brain of patients with epilepsy and rat brain upon seizures. We have shown that seizure-induced GA dispersion can be reversible, suggesting that enhanced neuronal activity induces Golgi reorganisation that is involved in aberrant neuronal plasticity processes that underlie epilepsy. Moreover, our results revealed that elevated cytosolic Ca2+ is indispensable for these KA-induced morphological alterations of GA in vitro.

Predictors of Class I epilepsy surgery outcome in tumour-related chronic temporal lobe epilepsy in adults.

OBJECTIVE: Temporal lobe tumours, especially low-grade gliomas and glioneuronal tumours, are common causes of seizures in patients referred for epilepsy surgery. We here present our experience of surgical treatment of patients with intractable chronic epilepsy associated with temporal lobe tumours, focusing on the long-term surgical outcomes and the features associated with better seizure control. METHODS: In this study, we retrospectively analysed 44 consecutive patients from a total of 182 with refractory temporal lobe epilepsy presenting with long-term intractable epilepsy due to a temporal lobe tumour who were surgically treated at our institution between 2005 and 2015 with post-surgical follow-up of at least two years. All patients underwent a standard pre-surgical evaluation that included: history and physical examination with a description of the seizure semiology, serial scalp EEG recording, brain MR imaging, and a detailed neuropsychological evaluation. Our surgical strategy comprised tumour resection, and combined mesial temporal and neocortical resection in most cases. RESULTS: No patient died during surgery or the postoperative course. Seven patients had postoperative complications, of whom two had permanent hemiparesis due to ischaemic stroke. At the final follow-up, a favourable seizure outcome (Engel Class I) was found in 37 patients (84%), including 31 (70.5%) in Engel Class IA (excellent result). Two (4.5%) patients presented with an Engel Class II outcome (unfavourable outcome). Five patients (11.5%) were in Engel Classes III or IV (surgical failure). We found that complete resection of the hippocampus along with tumour and temporal pole removal was strongly associated with seizure freedom (p = 0.015). Pathological diagnosis was also a significant prognostic indicator of tumour-related seizure freedom. Patients with a diagnosis of a glioneuronal tumour benefited from more seizure freedom after resection compared to those who had a low-grade glioma (p = 0.024). CONCLUSION: The most appropriate management of tumour-related chronic temporal lobe epilepsy in adults appears to be tai-lored temporal lobe resection including tumour and hippocampal complex removal. Surgical treatment of tumoural temporal lobe epilepsy demonstrates excellent results in terms of seizure improvement, especially in patients with glioneuronal tumours.

Social Perception in Mesial Temporal Lobe Epilepsy: Interpreting Social Information From Moving Shapes and Biological Motion.

Dysfunction in the understanding of social signals has been reported in persons with epilepsy, which may partially explain lower levels of life satisfaction in this patient population. Extensive assessment is necessary, particularly when the mesial temporal lobe, responsible for emotion processing, is affected. The authors examined multiple levels of social perception in patients with mesial temporal lobe epilepsy (MTLE), including judgments of point-light motion displays of human communicative interactions (Communicative Interactions Database-5 Alternative Forced Choice format) and theory-of-mind processes evaluated using geometric shapes (Frith-Happé animations [FHA]). This case-control study included MTLE patients with anterior temporal lobectomies (ATL+) (N=19), MTLE patients without lobectomies (ATL-) (N=21), and healthy controls (HCs) (N=20). Both groups of MTLE patients were less efficient in recognizing goal-directed and mentalizing interactions of FHA compared with HC subjects. The ATL+ group attributed emotions to FHA less accurately than HC subjects. Both the ATL- and ATL+ groups classified individual point-light animations more often as communicative than the HC group. ATL+ patients were also less efficient in interpreting point-light animations in terms of individual actions than the HC group. The number of years of epilepsy duration was inversely correlated with recognition of FHA interactions. The mean number of seizures was inversely correlated with the interaction identification in point-light stimuli. Patients with MTLE, irrespective of surgical treatment, present impaired social perception in domains assessed with abstract moving shapes or nonabstract biological motion. This impairment may be the basis of problems faced by patients reporting difficulties in understanding the intentions and feelings of other individuals.

Gaze matters! The effect of gaze direction on emotional enhancement of memory for faces in patients with mesial temporal lobe epilepsy.

PURPOSE: The aim of the study was to examine if gaze and emotional expression, both highly self-relevant social signals, affect the recollection accuracy of perceived faces in patients with mesial temporal lobe epilepsy (MTLE). METHODS: Forty patients with MTLE (twenty-one without surgery and nineteen after anterior temporal lobectomy) as well as twenty healthy controls (HC) took part in the study. We used a set of 64 facial stimuli: 32 neutral and 32 emotional displays (16 fearful; 16 angry) from well-established affective stimuli databases. Half of the faces in each condition had eyes directed straight and half - away from the observer. Participants performed a gender identification task, and then, after a 45-minute delay were asked to identify the previously seen stimuli, presented among a new set of photos. RESULTS: Increased automatic learning of angry and fearful compared to neutral expressions was found in HC. There was no emotional enhancement of memory in MTLE but an increased learning for faces with averted than direct gaze. CONCLUSION: Our results expand on previous research by demonstrating that emotion expression and gaze direction can affect memory of faces. The study supports the hypothesis that healthy individuals and patients with temporal lobe abnormalities present different patterns of emotional gazes processing. The potential consequences of altered emotional gaze processing and social cognition impairments need to be further investigated to improve the quality of life of patients with MTLE.

The prevalence of orodental trauma during epileptic seizures in terms of dental treatment - Survey study.

INTRODUCTION: Epilepsy is one of the most common neurological disorders. Seizures that occur during attacks may lead to head injuries. It is crucial to establish proper prophylactic management against trauma occurrence, as nowadays prevention is not sufficient. AIM: Assessment of the frequency of head and intraoral trauma during epileptic seizures and to evaluate factors that may predispose to injuries. MATERIAL AND METHODS: The questionnaire was carried out among 106 patients with epilepsy. Survey conducted questions regarding development of the disease and occurrence of orodental and head trauma. Results were statistically analyzed with the chi-square test (p<0.05). RESULTS: 52.4% of subjects admitted the occurrence of oral trauma during epileptic seizures. The most common were lips, tongue or cheeks injuries. 18% patients suffered from tooth crack and 17% from tooth fracture. 50% of respondents suffered from head trauma during seizures: 41% patients reported bruises, 39% burns, 37% wounds, 10% nose fractures, 7% eye socket trauma and 3% skull crack. 14.1% of respondents experienced dentist refusal to undertake treatment, while 4% of patients had epileptic attack during dental procedures. CONCLUSIONS: Dental trauma is common result of epileptic seizures. It is necessary to implement prophylactic management to prevent hard and soft tissues injuries, for example by using custom-made mouthguards. Moreover, specially designed dental programs for this group of patients should be provided.

Differences in quality of life of women and men with drug-resistant epilepsy in Poland.

PURPOSE: The aim of the study was to assess the differences in health-related quality of life in groups of men and women suffering with drug-resistant epilepsy and to determine which factors influence quality of life. METHODS: The examined group consisted of 64 subjects with drug-resistant epilepsy - 31 men and 33 women. The mean duration of epilepsy was 17.56±8.92 and 19±9.56years, respectively. The following diagnostic tools were used: QOLIE-31-P, Wechsler Adult Intelligence Scale - Revised (WAIS-R (PL)), and Hamilton Rating Scale for Depression (HRSD). RESULTS: Scores in QOLIE-31-P did not differ significantly between groups of men and women with drug-resistant epilepsy; however, a more detailed analysis revealed certain disparities. Multiple regression analyses indicated that some distinct factors were associated with quality of life in each sex. In the group of women, there were no significant predictors of their quality of life. Among the group of men, depression intensity was the only statistically significant QoL predictor, explaining 16% of the variance (adjusted R(2)=0.16, F(6, 24)=19.7, p<0.01). Moreover, patients with depression had lowered scores in the Emotional Well-Being and Energy/Fatigue subscales, regardless of the sex. CONCLUSION: The study revealed that, despite similar scores in QOLIE-31-P, specific factors may differentially affect the quality of life of men and women with drug-resistant epilepsy in Poland. Nevertheless, replication of these results with a larger number of participants is needed for a more definitive conclusion.

Navigating Social Waters: Understanding Theory-of-Mind Challenges in Patients with Mesial Temporal Lobe Epilepsy.

Background: Temporal lobe epilepsy is a common neurological disease that affects many areas of patients' lives, including social competence. The aim of the study was to assess theory of mind in patients with temporal lobe epilepsy and to investigate the demographic and clinical factors associated with this function. Methods: A total of 65 participants took part in the study, which included 44 patients with epilepsy and 21 demographically matched healthy individuals. The following neuropsychological tests were used to examine theory of mind: the Faux Pas Test, the Hinting Task, the Emotion Comprehension Test, and a cognitive function screen, the Montreal Cognitive Assessment. Results: Patients with epilepsy scored lower on all measures of the theory-of-mind tests. Moreover, in the clinical group, numerous moderate and strong correlations were found between the theory-of-mind tests and education, age at onset of epilepsy, lateralization of epileptic focus, cognitive status, and, to a lesser degree, number of anti-epileptic drugs, frequency of seizures, and age. In contrast, in the control group, significant correlations were found mostly between the theory-of-mind tests and sex, and, to a lesser degree, age. Education and cognitive functioning were not associated. Conclusions: Patients with epilepsy experience difficulties in theory of mind, which may have a negative impact on the quality of their social relationships. The level of theory-of-mind abilities correlates with particular clinical and demographic indicators. Recognizing these issues allows clinicians to implement tailored interventions, potentially improving patients' quality of life.

Determinants of the Quality of Life in Patients with Drug-Resistant Temporal Lobe Epilepsy: A Comparison of the Results before and after Surgery.

Drug-resistant temporal lobe epilepsy is associated with a reduction in the quality of life of patients. The aim of this study was to compare the quality of life before and after the surgical treatment of epilepsy and to assess factors that may affect the well-being of patients after surgery. The study involved 168 patients with drug-resistant temporal lobe epilepsy. All of them were examined twice: once before and again one year after surgery. Two questionnaires were used in the study: the Quality of Life in Epilepsy Inventory-Patient-Weighted and Hospital Anxiety and Depression Scale and one that collected data on selected demographic and clinical variables. The results showed that patients scored significantly higher in quality of life and lower in depression and anxiety after surgery; however, this only applied to patients with a good outcome of treatment (Engel Class I and Class II). Patients with an unfavorable outcome of surgical treatment (Engel Class III and Class IV) achieved significantly worse results in all examined variables. Correlational analysis showed a relationship between select aspects of quality of life and the level of depression and anxiety, as well as the frequency of seizures and age at epilepsy onset. There was no significant relationship with age, sex, education, or number of prescribed antiepileptic drugs. The study confirms the significant relationship between the quality of life and the effectiveness of surgical treatment, indicating the relationship between patients' well-being and selected clinical indicators.

Experience of adverse events with cerebral propofol testing in patients with drug resistant epilepsy.

The aim of this study was to assess the type and frequency of adverse events during the Wada test conducted with propofol as an anaesthetic agent. In total, 122 patients with temporal lobe epilepsy underwent the Wada test with propofol between 2006 and 2016 as part of presurgical evaluation at the Department of Neurosurgery of the Medical University of Warsaw. The Wada test was conducted bilaterally on 118 patients (236 cases). In four cases, due to complications, the test was conducted only unilaterally, which resulted in a total of 240 cases. Those cases were further analysed for the presence of adverse events. In all cases, intracranial circulation angiography (via the transfemoral approach) was performed before memory and language testing. Of the 122 patients, adverse events were observed in 75 patients (61.4%). Serious complications were notably rare and observed only in two patients (1.6%): one patient had a carotid artery dissection, and the other had a pseudoaneurysm at the puncture site. Mild adverse events (e.g., shivers or pain of the eye) were highly common - we observed them in 71 patients (58%), but they were short-term and well-tolerated by the subjects. Two patients (1.6%) had a seizure during the Wada test. Most of the adverse events occurring during the Wada test with propofol were mild and short-lived. Considering a small risk of serious damage to health, this procedure can be perceived as a good method for assessing language and memory in a fraction of the epilepsy surgery candidates.

Ectopic cerebellum in anterior cranial fossa: Report of a unique case associated with skull congenital malformations and epilepsy.

An isolated, well-differentiated ectopic cerebellum arising outside the posterior fossa is extremely rare. We present a unique case of ectopic cerebellum in 25-year-old woman with hypertelorism, skull deformation, and a longstanding history of epileptic seizures. Magnetic resonance imaging revealed a mass lesion at the base of the frontal lobes with no apparent connections to the adjacent brain structures. Total resection of the lesion was performed. On gross inspection, its surface resembled cerebellar cortex with densely packed folia. Histologically, the cerebellar cortex was composed of well-differentiated external molecular, Purkinje cell, and internal granular cell layers. The deeper part of white matter displayed the features of neuroglial, hamartomatouslike abnormalities. There were numerous neuronal and/or glial heterotopias ranging from single dysplastic neurons to well-circumscribed clusters of neuronal and/or glial cells surrounded by neuropil. Some large neurons looked like mature ganglion cells, Purkinje cells, or dentate neurons. Large irregular islands of heterotopic tissue displaying well-differentiated cerebellar cortex could also be seen. Other parts of the ectopic cerebellum revealed loosening of tissue with dispersed glioneuronal elements. The ectopic brain tissue may arise from disturbed migration of primitive pluripotent stem cells during embryogenesis. The presented case of cerebellar ectopia associated with skull congenital malformations exhibited multiple dysontogenetic abnormalities. To our knowledge, this is the first report of totally isolated, well-differentiated ectopic cerebellum in the anterior cranial fossa accompanied by skull deformation and epilepsy.

System for automatic heart rate calculation in epileptic seizures.

This article presents a comprehensive system for automatic heart rate (HR) detection. The system is robust and resistant to disturbances (noise, interferences, artifacts) occurring mainly during epileptic seizures. ECG signal filtration (IIR) and normalization due to skewness and standard deviation were used as preprocessing steps. A key element of the system is a reference QRS complex pattern calculated individually for each ECG recording. Next, a cross-correlation of the reference QRS pattern with short, normalized ECG windows is calculated and the maxima of the correlation are found (R-wave locations). Determination of the RR intervals makes possible calculation of heart rate changes and also heart rate variability (HRV). The algorithm was tested using a simulation in which a noise of an amplitude several times higher than ECG standard deviation levels was added. The proposed algorithm is characterized by high QRS detection accuracy, and high sensitivity and specificity. The algorithm proved to be useful in clinical practice, where it was used to automatically determine HR for ECG signals recorded before and during 58 focal seizures in 56 adult patients with intractable temporal lobe epilepsy.

Polymorphism of the multidrug resistance 1 gene MDR1 G2677T/A (rs2032582) and the risk of drug-resistant epilepsy in the Polish adult population.

The aim of this study was to analyse the frequency of genotypes and alleles of single-nucleotide polymorphism (SNP)-G2677T/A (rs2032582) of MDR1 gene and to investigate the significance this genetic variation exerts on drug-resistant epilepsy (DRE) in the Polish adult population. The study comprised 340 patients treated for DRE and 240 patients treated for drug-responsive epilepsy. Three hundred and sixty disease-free individuals were used as controls. Genomic DNA was isolated, and the SNP G2677T/A of MDR1 was determined by High-Resolution Melter technique. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for each genotype and allele. In this paper, we have demonstrated that A allele of SNP G2677T/A of MDR1 may reduce the risk of DRE (OR 0.44; 95% CI 0.33-0.58, p < 0.0001), whereas allele G itself may be a risk factor for this disease. No differences were found in the distribution of the genotypes and alleles in the studied groups, depending on sex as well as on concomitant diseases (p > 0.05). G2677T/A polymorphism of MDR1 may play a significant role in the development of DRE in the Polish patients.

Associations between MDR1 C3435T polymorphism and drug-resistant epilepsy in the Polish population.

Epilepsy is a common neurological disorder. About one-third of epileptic patients demonstrate multidrug resistance (MDR) phenotype and develop drug-resistant epilepsy (DRE). Single nucleotide polymorphism (SNP) C3435T (rs1045642), identified in the MDR1 gene, is associated with an increased intestinal expression of P-glycoprotein (P-gp) which affects the levels of anti-epileptic drugs in plasma. The reported study was designed to explore associations between the MDR1-C3435T gene SNP and the risk of DRE in the Polish population. The C3435T polymorphism of MDR1 gene was investigated by the PCR-RFLP technique in 74 patients with DRE and 70 age- and sex-matched non-DRE controls. Blood samples were obtained from patients with drug-resistant epilepsy, treated at the Department of Neurological Surgery, Medical University in Warsaw between the years 2011 and 2012. Odds ratios (ORs) and 95 % confidence intervals (CIs) were calculated for each genotype and allele. Genotype distribution of C3435T polymorphism of MDR1 gene was compared between the DRE patients and controls with significant differences (p < 0.05) between the two investigated groups. A possible association was observed between DRE and the presence of 3435C allele. The 3435C allele was found in 69 % of DRE cases and in 48 % of the used controls. The variant 3435T allele of MDR1 decreased the risk of drug-resistant epilepsy [odds ratio (OR) 0.41; 95 % confidence interval (CI) 0.26-0.67]. The results indicate that the C3435T polymorphism of MDR1 gene may be associated with the incidence of DRE observed in the Polish population.

Social cognition in neuropsychiatric populations: a comparison of theory of mind in schizophrenia and mesial temporal lobe epilepsy.

Social cognition deficits are observed both in patients with schizophrenia (SCZ) and in patients with mesial temporal lobe epilepsy (MTLE). This may be due to dysfunction of the amygdala network, which is a common feature of both diseases. In this study, SCZ (n = 48) or MTLE (n = 31) and healthy controls (HC, n = 47) completed assessments of mentalising (Reading Mind in the Eyes Test, RMET) and basic cognitive processing, e.g., working memory, executive functions and psychomotor speed (Trail-Making Test B and Digit Symbol). SCZ were also assessed with the Positive And Negative Syndrome Scale (PANSS). We found that the RMET scores of the two clinical groups were similar (p > 0.05) and lower than in the HCs (SCZ: p < 0.05; MTLE: p < 0.001). In the next step, SCZ were split into two groups with respect to the level of symptoms. Analysis of the RMET scores revealed no differences between the HC (M = 25.7 ± 4.1) and POS-LO (M = 25.3 ± 4.8); both groups outperformed the POS-HI group (M = 21.3 ± 5.2) and the MTLE group (M = 20.8 ± 4.6). No differences were found for the median-split with regard to negative symptoms. In SCZ, the mind-reading deficit appears to be associated with the level of positive symptoms. Both POS-HI and MTLE patients present significant mentalising deficits compared to healthy controls.

Epigenetics of Epileptogenesis-Evoked Upregulation of Matrix Metalloproteinase-9 in Hippocampus.

Enhanced levels of Matrix Metalloproteinase-9 (MMP-9) have been implicated in the pathogenesis of epilepsy in humans and rodents. Lack of Mmp-9 impoverishes, whereas excess of Mmp-9 facilitates epileptogenesis. Epigenetic mechanisms driving the epileptogenesis-related upregulation of MMP-9 expression are virtually unknown. The aim of this study was to reveal these mechanisms. We analyzed hippocampi extracted from adult and pediatric patients with temporal lobe epilepsy as well as from partially and fully pentylenetetrazole kindled rats. We used a unique approach to the analysis of the kindling model results (inclusion in the analysis of rats being during kindling, and not only a group of fully kindled animals), which allowed us to separate the molecular effects exerted by the epileptogenesis from those related to epilepsy and epileptic activity. Consequently, it allowed for a disclosure of molecular mechanisms underlying causes, and not consequences, of epilepsy. Our data show that the epileptogenesis-evoked upregulation of Mmp-9 expression is regulated by removal from Mmp-9 gene proximal promoter of the two, interweaved potent silencing mechanisms-DNA methylation and Polycomb Repressive Complex 2 (PRC2)-related repression. Demethylation depends on a gradual dissociation of the DNA methyltransferases, Dnmt3a and Dnmt3b, and on progressive association of the DNA demethylation promoting protein Gadd45ß to Mmp-9 proximal gene promoter in vivo. The PRC2-related mechanism relies on dissociation of the repressive transcription factor YY1 and the dissipation of the PRC2-evoked trimethylation on Lys27 of the histone H3 from the proximal Mmp-9 promoter chromatin in vivo. Moreover, we show that the DNA hydroxymethylation, a new epigenetic DNA modification, which is localized predominantly in the gene promoters and is particularly abundant in the brain, is not involved in a regulation of MMP-9 expression during the epileptogenesis in the rat hippocampus as well as in the hippocampi of pediatric and adult epileptic patients. Additionally, we have also found that despite of its transient nature, the histone modification H3S10ph is strongly and gradually accumulated during epileptogenesis in the cell nuclei and in the proximal Mmp-9 gene promoter in the hippocampus, which suggests that H3S10ph can be involved in DNA demethylation in mammals, and not only in Neurospora. The study identifies MMP-9 as the first protein coding gene which expression is regulated by DNA methylation in human epilepsy. We present a detailed epigenetic model of the epileptogenesis-evoked upregulation of MMP-9 expression in the hippocampus. To our knowledge, it is the most complex and most detailed mechanism of epigenetic regulation of gene expression ever revealed for a particular gene in epileptogenesis. Our results also suggest for the first time that dysregulation of DNA methylation found in epilepsy is a cause rather than a consequence of this condition.

[Motor-evoked potentials in patients with diabetes mellitus type 1]. / Motoryczne potencjaly wywolane u chorych na cukrzyce typu 1.

BACKGROUND AND PURPOSE: The aim of the study was to assess the function of the central motor pathway in young patients with diabetes mellitus type 1 by use of transcranial and paravertebral magnetic stimulation. MATERIALS AND METHODS: MEPs were recorded in 68 young patients (25+/-5.69 years), with diabetes mellitus type 1, from muscles: abductor digiti minimi and abductor hallucis (AH). Central motor conduction time (CMCT) was calculated by subtracting cortical latency (CL) after transcranial stimulation from the motor nerve conduction time (MNCT) after paravertebral stimulation. The obtained results were compared with normative data from the group of 36 healthy volunteers, matched for age and height. Statistical comparison of CMCT between diabetic and control groups was performed. RESULTS: There were no significant differences between the diabetics and control means of CMCT. Also, we were unable to elicit the MEPs cortically from AH muscle in 19 (27.9%) of diabetic patients and only in 3 (8.3%) controls. CONCLUSION: CMCT is normal in patients below 40 years of age, in whom the MEPs after transcranial stimulation can be elicited. Lack of MEPs in lower limb muscles following transcranial stimulation in almost 30% of patients in the presence of MEPs in upper limbs may indirectly suggest the dysfunction of central motor conduction in those cases.

[The effect of chronic Vagus Nerve Stimulation (VNS) on the central conduction time assessed by multimodal evoked potentials in patients with drug resistant epilepsy: preliminary report]. / Wplyw przewleklej Stymulacji Nerwu Blednego (SNB) u chorych z padaczka lekooporna na centralny czas przewodzenia, oceniany badaniami multimodalnych potencjalów wywolanych. Doniesienie wstepne.

Changes over time in evoked potentials of various modality (VEP, SSEP and BAEP) were analyzed in 3 patients, submitted to chronic Vagus Nerve Stimulation (VNS) due to drug resistant epilepsy. The aim of a study was to establish which cerebral structures are most prone to change their baseline electrophysiological status in consequence of chronic VNS. Evoked potentials were examined before the Vagus Nerve Stimulator implantation and at arbitrarily defined follow-ups several months after the implantation. Preliminary results obtained in a small group of 3 patients suggest a possible prolongation of the central conduction time in the examined modalities of evoked potentials due to the VNS treatment. A hypothetical mechanism of antiepileptic VNS action might be related to the permanent stimulation of brainstem and cortical structures that limit seizures propagation through hyperpolarisation both at the cortical level and in subcortical structures.

[Vagus nerve stimulation (VNS) in the treatment of drug-resistant epilepsy. A 4-year follow-up evaluation of VNS treatment efficacy]. / Stymulacja nerwu blednego (SNB) w leczeniu lekoopornej padaczki. Ocena skutecznosci po 4 latach leczenia.

OBJECTIVES: Vagus nerve stimulation (VNS) is an alternative non-destructive surgical treatment for patients with medically intractable epilepsy. Neither the rationale nor proper indications for this treatment modality have been fully established yet. AIM OF THE STUDY: To assess the long-term efficacy of chronic VNS. MATERIAL: A series of 6 patients with drug-resistant epilepsy, subjected to VNS therapy. (4 females, 2 males, mean age 35.5 years, 3 patients with focal epilepsy, 3 with non-focal epilepsy, mean history of seizures 10 years, seizures frequency 10-400/per month). METHOD: An open-label prospective study with a 4-year follow-up. RESULTS: At a 4-year follow-up one patient (with non-focal epilepsy) was seizure-free, with only rare episodes of aura (Engel Ia), while in another one (with bitemporal epilepsy) seizures frequency remained unchanged with VNS (Engel IVb). In the remaining 4 cases (one with bitemporal, one with parietal, and two with non-focal epilepsy) the mean overall reduction in seizures frequency as compared to the baseline was 60% (Engel IIIa). VNS resulted in a reduction of seizures by 90% in a patient with a history of an unsuccessful anterior callosotomy. CONCLUSIONS: 1. VNS was found to reduce both the frequency of seizures (an overall 60% reduction in seizures frequency) and the duration of post-seizure consciousness disturbances in focal and non-focal epilepsies, but seizures-free state could be obtained in only one out of six patients. 2. A previous unsuccessful callosotomy did not prevent a good anticonvulsant effect in one patient. 3. The anticonvulsant effect of VNS was cumulative over time during the first 3 years postoperatively, then it tended to reach a plateau. 4. The best clinical outcome was positively correlated with the currents 1.5-2.0 mA. No significant correlation was noted for the current adjustments at the level of 2.0-3.5 mA. 5. Since no difference between the two stimulation patterns tested (30 s stimulation + 5 min break vs. 14 s + 3 min) was found as regards the anticonvulsant action of VNS, the latter pattern was subsequently used as the one more sparing the battery.

Matrix metalloproteinase-9 (MMP-9) in human intractable epilepsy caused by focal cortical dysplasia.

Focal cortical dysplasia (FCD) is a developmental brain disorder characterized by localized abnormalities of cortical layering and neuronal morphology. It is associated with pharmacologically intractable forms of epilepsy in both children and adults. The mechanisms that underlie FCD-associated seizures and lead to the progression of the disease are unclear. Matrix metalloproteinases (MMPs) are enzymes that are able to influence neuronal function through extracellular proteolysis in various normal and pathological conditions. The results of experiments that have used rodent models showed that extracellular MMP-9 can play an important role in epileptogenesis. However, no studies have shown that MMP-9 is involved in the pathogenesis of human epilepsy. The aim of the present study was to determine whether MMP-9 plays a role in intractable epilepsy. Using an unbiased antibody microarray approach, we found that up regulation of MMP-9 is prominent and consistent in FCD tissue derived from epilepsy surgery, regardless of the patient's age. Additionally, an up regulation of MMP-1, -2, -8, -10, and -13 was found but was either less pronounced or limited only to adult cases. In the dysplastic cortex, immunohistochemistry revealed that the highest MMP-9 immuno reactivity occurred in the cytoplasm of abnormal neurons and balloon cells. The neuronal over expression of MMP-9 also occurred in sclerotic hippocampi that were excised together with the dysplastic cortex, but sclerotic hippocampi were free of dysplastic features. In both locations, MMP-9 was also found in reactive astrocytes, albeit to a lesser extent. At the subcellular level, increased MMP-9 immunoreactivity was prominently upregulated at synapses. Thus, although upregulation of the enzyme in FCD is not causally linked to the developmental malformation, it may be a result of ongoing abnormal synaptic plasticity. The present findings support the hypothesis of the pathogenic role of MMP-9 in human epilepsy and may stimulate discussions about whether MMPs could be novel therapeutic targets for intractable epilepsy.

Unclassified glioneuronal tumor with advanced lipidization.

Lipidization is observed only occasionally in primary neuroectodermal tumors of the central nervous system. It may reflect lipomatous transformation of tumor cells into xanthomatous and/or adipocyte-like cells. We report a unique case of mixed glioneuronal tumor with marked lipomatous changes in a young patient with intractable epilepsy. MRI revealed a well-circumscribed lesion in the right temporal lobe. Histopathological findings showed the pleomorphic tumor with numerous cells containing large lipid droplets, resembling mature adipocytes, that were arranged in clusters or scattered within the neoplastic tissue. The tumor was composed of both glial and neuronal elements. Some tumor cells displayed features intermediate between glial and neuronal cells. The reticulin fibers were limited to blood vessels. Mitotic figures, vascular proliferation, and necrosis were absent, and MIB-1 labeling index was less than 1%. Diffuse immunoreactivity for GFAP and S100-protein was observed. In some heavily lipidized cells, the lipid droplets were surrounded by a cytoplasmic rim of GFAP immunoreactivity. Numerous cells exhibited immunostaining for NSE and synaptophysin. This is the first documented case of glioneuronal tumor with extensive lipomatous transformation, which might be considered as a heavily lipidized unclassified pleomorphic glioneuronal tumor or a variant of lipoganglioglioma with marked pleomorphism and severe lipidization.