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Aim: Matrix metalloproteinases (MMPs) and their endogenous tissue inhibitors (TIMPs) control proteolysis within the extracellular matrix (ECM) of the brain. Dysfunction of this enzymatic system due to brain inflammation can disrupt the blood‐brain barrier (BBB) and has been implicated in the pathogenesis of epilepsy. However, this has not been extensively studied in the epileptogenic human brain. Methods: We investigated the expression and cellular localization of major MMPs (MMP2, MMP3, MMP9 and MMP14) and TIMPs (TIMP1, TIMP2, TIMP3 and TIMP4) using quantitative real‐time polymerase chain reaction (RT‐PCR) and immunohistochemistry in resected epileptogenic brain tissue from patients with tuberous sclerosis complex (TSC), a severe neurodevelopmental disorder characterized by intractable epilepsy and prominent neuroinflammation. Furthermore, we determined whether anti‐inflammatory microRNAs, miR146a and miR147b, which can regulate gene expression at the transcriptional level, could attenuate dysregulated MMP and TIMP expression in TSC tuber‐derived astroglial cultures. Results: We demonstrated higher mRNA and protein expression of MMPs and TIMPs in TSC tubers compared to control and perituberal brain tissue, particularly in dysmorphic neurons and giant cells, as well as in reactive astrocytes, which was associated with BBB dysfunction. More importantly, IL‐1β‐induced dysregulation of MMP3, TIMP2, TIMP3 and TIMP4 could be rescued by miR146a and miR147b in tuber‐derived TSC cultures. Conclusions: This study provides evidence of dysregulation of the MMP/TIMP proteolytic system in TSC, which is associated with BBB dysfunction. As dysregulated MMP and TIMP expression can be ameliorated in vitro by miR146a and miR147b, these miRNAs deserve further investigation as a novel therapeutic approach. [ABSTRACT FROM AUTHOR]

Aim: Matrix metalloproteinases (MMPs) and their endogenous tissue inhibitors (TIMPs) control proteolysis within the extracellular matrix (ECM) of the brain. Dysfunction of this enzymatic system due to brain inflammation can disrupt the blood‐brain barrier (BBB) and has been implicated in the pathogenesis of epilepsy. However, this has not been extensively studied in the epileptogenic human brain. Methods: We investigated the expression and cellular localization of major MMPs (MMP2, MMP3, MMP9 and MMP14) and TIMPs (TIMP1, TIMP2, TIMP3 and TIMP4) using quantitative real‐time polymerase chain reaction (RT‐PCR) and immunohistochemistry in resected epileptogenic brain tissue from patients with tuberous sclerosis complex (TSC), a severe neurodevelopmental disorder characterized by intractable epilepsy and prominent neuroinflammation. Furthermore, we determined whether anti‐inflammatory microRNAs, miR146a and miR147b, which can regulate gene expression at the transcriptional level, could attenuate dysregulated MMP and TIMP expression in TSC tuber‐derived astroglial cultures. Results: We demonstrated higher mRNA and protein expression of MMPs and TIMPs in TSC tubers compared to control and perituberal brain tissue, particularly in dysmorphic neurons and giant cells, as well as in reactive astrocytes, which was associated with BBB dysfunction. More importantly, IL‐1β‐induced dysregulation of MMP3, TIMP2, TIMP3 and TIMP4 could be rescued by miR146a and miR147b in tuber‐derived TSC cultures. Conclusions: This study provides evidence of dysregulation of the MMP/TIMP proteolytic system in TSC, which is associated with BBB dysfunction. As dysregulated MMP and TIMP expression can be ameliorated in vitro by miR146a and miR147b, these miRNAs deserve further investigation as a novel therapeutic approach. [ABSTRACT FROM AUTHOR]

Background: The proteasome is a multisubunit enzyme complex involved in protein degradation, which is essential for many cellular processes. During inflammation, the constitutive subunits are replaced by their inducible counterparts, resulting in the formation of the immunoproteasome.Methods: We investigated the expression pattern of constitutive (β1, β5) and immunoproteasome (β1i, β5i) subunits using immunohistochemistry in malformations of cortical development (MCD; focal cortical dysplasia (FCD) IIa and b, cortical tubers from patients with tuberous sclerosis complex (TSC), and mild MCD (mMCD)). Glial cells in culture were used to elucidate the mechanisms regulating immunoproteasome subunit expression.Results: Increased expression was observed in both FCD II and TSC; β1, β1i, β5, and β5i were detected (within cytosol and nucleus) in dysmorphic neurons, balloon/giant cells, and reactive astrocytes. Glial and neuronal nuclear expression positively correlated with seizure frequency. Positive correlation was also observed between the glial expression of constitutive and immunoproteasome subunits and IL-1β. Accordingly, the proteasome subunit expression was modulated by IL-1β in human astrocytes in vitro. Expression of both constitutive and immunoproteasome subunits in FCD II-derived astroglial cultures was negatively regulated by treatment with the immunomodulatory drug rapamycin (inhibitor of the mammalian target of rapamycin (mTOR) pathway, which is activated in both TSC and FCD II).Conclusions: These observations support the dysregulation of the proteasome system in both FCD and TSC and provide new insights on the mechanism of regulation the (immuno)proteasome in astrocytes and the molecular links between inflammation, mTOR activation, and epilepsy. [ABSTRACT FROM AUTHOR]

Purpose: miR21, miR146, and miR155 represent a trio of microRNAs which has been shown to play a key role in the regulation of immune and inflammatory responses. In the present study, we investigated the differential expression and clinical significance of these three miRNAs in glioneuronal tumors (gangliogliomas, GGs) which are characterized by prominent activation of the innate immune response. Methods: The expression levels of miR21, miR146, and miR155 were evaluated using Taqman PCR in 34 GGs, including 15 cases with sufficient amount of perilesional cortex. Their expression was correlated with the tumor features and the clinical history of epilepsy. In addition, in situ hybridization was used to evaluate their cellular distribution in both tumor and peritumoral cortex. Results: Increased expression of miR146a was observed in both tumor and peritumoral cortex compared to control samples. miR146a was detected in both neuronal and astroglial cells. Tumor and peritumoral miR146a expression was negatively correlated with frequency of seizures and the density of activated microglial cells. Neuronal and astroglial expression was observed for both miR21 and miR155 with increased expression of miR21 within the tumor and miR155 in the peritumoral region. Negative correlations were observed between the miRNA levels and the expression of putative targets within the astroglial component of the tumor. Conclusion: We report a differential regulation of three miRNAs, known to be related to inflammation, in both tumor and peritumoral cortex of patients with GG. Moreover, our findings suggest a functional relationship between miR146a expression and epilepsy, either directly in epileptogenesis or as modulation of seizure activity. [ABSTRACT FROM AUTHOR]

Objective – In the Netherlands, presurgical screening for temporal lobe epilepsy (TLE) includes the intracarotid amobarbital procedure (IAP), consisting of two consecutive injections of amobarbital, ipsilateral and contralateral to the epileptic focus. We studied whether a bilateral IAP has added value to a unilateral, ipsilateral IAP. Methods – This population-based study included 183 consecutive patients referred for screening for TLE surgery who underwent bilateral IAP. Using multivariable modeling, we assessed the added value of bilateral IAP on the decision for surgery, resection size, amygdalohippocampectomy, post-operative seizure freedom, memory performance, and IQ change. Results – Given the results from the unilateral IAP, the bilateral IAP had added prognostic value for postoperative change in verbal memory ( P < 0.01) and verbal IQ ( P < 0.01), especially if patients had a left-sided focus. In contrast, information provided by the contralateral IAP was not associated with decision-making or surgical strategy. Conclusions – A bilateral IAP has added value in predicting post-operative verbal memory and IQ. A bilateral IAP is currently not used to guide surgical strategy, but may be used for this purpose when verbal capacity is of particular concern in patients with a left-sided focus. In other cases, IAP is best performed unilaterally. [ABSTRACT FROM AUTHOR]

Obsessive–compulsive disorder (OCD) is a chronic, disabling disorder. Psychosurgery may be indicated for a subset of patients for whom no conventional treatment is satisfactory. This paper focuses on the stereotactic subcaudate tractotomy (SST). Thus far, these procedures have been carried out using frame-based stereotactic techniques. However, modern – highly accurate – frameless stereotactic procedures have successfully been introduced in neurosurgical practice. We developed a novel frameless stereotactic subcaudate tractotomy procedure with promising initial results in a patient suffering from intractable OCD. This is the first report on frameless SST. Future studies should examine whether other ablative stereotactic psychosurgery procedures can be done using frameless stereotactic methods. [ABSTRACT FROM AUTHOR]

E. Aronica, J. A. Gorter, S. Redeker, M. Ramkema, W. G. M. Spliet, P. C. van Rijen, S. Leenstra and D. Troost (2004)Neuropathology and Applied Neurobiology30,000–000Distribution, characterization and clinical significance of microglia in glioneuronal tumours from patients with chronic intractable epilepsyCells of the microglia/macrophage lineage represent an important component of different brain tumours. However, there is little information about the microglia/macrophage cell system in glioneuronal tumours and its possible contribution to the high epileptogenecity of these lesions. In the present study, the distribution of cells of the microglia/macrophage lineage was studied by immunocytochemistry for CD68 and human leucocyte antigen (HLA)-DR in a group of glioneuronal tumours, including gangliogliomas (GG,n = 30), and dysembryoplastic neuroepithelial tumours (DNT,n = 17), from patients with chronic intractable epilepsy. A significant number of microglia/macrophage cells were observed in the large majority of glioneuronal tumours, both within the tumour and in the peritumoral region. Activated microglial cells positive for HLA-DR were localized around blood vessels and clustered around tumour neuronal cells. The density of activated microglial cells correlated with the duration of epilepsy, as well as with the frequency of seizures prior to surgical resection. These observations indicate that the presence of cells of the microglial/macrophage cell system is a feature of glioneuronal tumours and is functionally related to epilepsy, either directly in epileptogenesis or through activation following seizure activity. [ABSTRACT FROM AUTHOR]

The conductivity of the human skull plays an important role in source localization of brain activity, because it is low as compared to other tissues in the head. The value usually taken for the conductivity of skull is questionable. In a carefully chosen procedure, in which sterility, a stable temperature, and relative humidity were guaranteed, we measured the (lumped, homogeneous) conductivity of the skull in five patients undergoing epilepsy surgery, using an extended four-point method. Twenty-eight current configurations were used, in each of which the potential due to an applied current was measured. A finite difference model, incorporating the geometry of the skull and the electrode locations, derived from CT data, was used to mimic the measurements. The conductivity values found were ranging from 32 mS/m to 80 mS/rn, which is much higher than the values reported in other studies. Causes for these higher conductivity values are discussed. [ABSTRACT FROM AUTHOR]

In patients suffering from temporal lobe epilepsy (TLE) a highly variable degree of hippocampal sclerosis (HS) can be observed. For standard neuropathological evaluation after hippocampal resection, neuronal cell loss in the hippocampal subareas is assessed (Wyler score 0–4) [Wyler et al. (1992) J Epilepsy 5: 220–225]. Other marked morphological changes in the sclerotic hippocampus are gliosis and loss of mossy fibers in the hilus and mossy fiber sprouting in the supragranular layer. In this study we quantified changes in mossy fiber density using Timm's stain in resected hippocampal tissue from patients with various degrees of sclerosis. We found that tissue specimens from patients without sclerosis (W0) show almost no mossy fiber sprouting. Patients with moderate sclerosis show sprouting without fiber loss in the hilus, whereas specimens from patients with severe sclerosis show sprouting as well as fiber loss in the hilus. Thus, analysis of mossy fiber abundance in hilus and supragranular layer by the rapid and simple Timm's stain is a sensitive measure for hippocampal sclerosis. It provides a reliable rapid tool for neuropathological evaluation, even if the tissue only contains dentate gyrus due to the sectioning procedure. [ABSTRACT FROM AUTHOR]