Andrzej Rysz

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 patients 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.

Single-class SVM and directed transfer function approach to the localization of the region containing epileptic focus

The paper presents the study concerning the application of a single-class support vector machine (SVM) and directed transfer function method for the localization of the region of the brain containing the epileptic focus on the basis of EEG registration. The results of the performed numerical experiments for the localization of the seizure focus in the brain will be demonstrated on the examples of EEG for few patients.

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 Gadd45β 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.

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.

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.

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.

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.

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.

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.