Venous 3D Phase Contrast Magnetic Resonance Angiography Increases Diagnostic Certainty in Children with Ventriculoperitoneal Shunt and Suspected Shunt Failure.

BACKGROUND: Clinical symptoms in children with suspected malfunction of ventriculoperitoneal shunt may not be specific and difficult to interpret. The presence or absence of ventricular enlargement on magnetic resonance imaging (MRI) does not reliably predict raised intracranial pressure (ICP) in these patients. Therefore, the aim was to investigate the diagnostic utility of 3D venous phase-contrast MR angiography (vPCA) in these patients. MATERIALS: The MR studies of two groups of patients at two different examination dates were retrospectively analyzed; one group without clinical symptoms on both examinations and one with symptoms of shunt dysfunction on one examination receiving surgery. Both MRI examinations had to have been performed including axial T2 weighted (T2-w) images and 3D vPCA. Two (neuro)radiologists evaluated T2-w images alone and in combination with 3D vPCA in terms of suspected elevated ICP. Interrater reliability, sensitivity and specificity were assessed. RESULTS: Compression of venous sinuses was seen significantly more often in patients with shunt failure (p = 0.00003). Consequently, evaluation of 3D vPCA and T2-w images increases sensitivity to 0.92/1.0 compared to T2-w images alone with 0.69/0.77, the interrater agreement for the diagnosis of shunt failure rises from κ = 0.71 to κ = 0.837. Concerning imaging markers, three groups could be identified in children with shunt failure. CONCLUSION: In accordance with the literature, the results show that ventricular morphology alone is an unreliable marker for elevated ICP in children with shunt malfunction. The findings confirmed 3D vPCA as a valuable supplemental diagnostic tool improving diagnostic certainty for children with unchanged ventricular size in cases of shunt failure.

Gliomas induce and exploit microglial MT1-MMP expression for tumor expansion.

Diffuse infiltration of glioma cells into normal brain tissue is considered to be a main reason for the unfavorable outcomes of patients with malignant gliomas. Invasion of glioma cells into the brain parenchyma is facilitated by metalloprotease-mediated degradation of the extracellular matrix. Metalloproteases are released as inactive pro-forms and get activated upon cleavage by membrane bound metalloproteases. Here, we show that membrane type 1 metalloprotease (MT1-MMP) is up-regulated in glioma-associated microglia, but not in the glioma cells. Overexpression of MT1-MMP is even lethal for glioma cells. Glioma-released factors trigger the expression and activity of MT1-MMP via microglial toll-like receptors and the p38 MAPK pathway, as deletion of the toll-like receptor adapter protein MyD88 or p38 inhibition prevented MT1-MMP expression and activity in cultured microglial cells. Microglial MT1-MMP in turn activates glioma-derived pro-MMP-2 and promotes glioma expansion, as shown in an ex vivo model using MT1-MMP-deficient brain tissue and a microglia depletion paradigm. Finally, MyD88 deficiency or microglia depletion largely attenuated glioma expansion in 2 independent in vivo models.

Minocycline reduces glioma expansion and invasion by attenuating microglial MT1-MMP expression.

Glioma cells release soluble factors, which induce the expression of membrane type 1 matrix metalloprotease (MT1-MMP) in tumor associated microglia and then exploit MT1-MMP mediated matrix degradation for invasion. Here, we show that minocycline blocked the increase in MT1-MMP expression and activity in cultivated microglia stimulated with glioma conditioned medium. Glioma growth within an organotypic brain slice preparation was reduced by minocycline and this reduction depended on the presence of microglia. Glioma growth in an experimental mouse model was strongly reduced by the addition of minocycline to drinking water, compared to untreated controls. Coherently, we observed in our orthotopic glioma implantation model, that MT1-MMP was abundantly expressed in glioma associated microglia in controls, but was strongly attenuated in tumors of minocycline treated animals. Overall, our study indicates that the clinically approved antibiotic minocycline is a promising new candidate for adjuvant therapy against malignant gliomas.

Adenosine receptors and cancer.

The A(1), A(2A), A(2B) and A(3) G-protein-coupled cell surface adenosine receptors (ARs) are found to be upregulated in various tumor cells. Activation of the receptors by specific ligands, agonists or antagonists, modulates tumor growth via a range of signaling pathways. The A(1)AR was found to play a role in preventing the development of glioblastomas. This antitumor effect of the A(1)AR is mediated via tumor-associated microglial cells. Activation of the A(2A)AR results in inhibition of the immune response to tumors via suppression of T regulatory cell function and inhibition of natural killer cell cytotoxicity and tumor-specific CD4+/CD8+ activity. Therefore, it is suggested that pharmacological inhibition of A(2A)AR activation by specific antagonists may enhance immunotherapeutics in cancer therapy. Activation of the A(2B)AR plays a role in the development of tumors via upregulation of the expression levels of angiogenic factors in microvascular endothelial cells. In contrast, it was evident that activation of A(2B)AR results in inhibition of ERK1/2 phosphorylation and MAP kinase activity, which are involved in tumor cell growth signals. Finally, A(3)AR was found to be highly expressed in tumor cells and tissues while low expression levels were noted in normal cells or adjacent tissue. Receptor expression in the tumor tissues was directly correlated to disease severity. The high receptor expression in the tumors was attributed to overexpression of NF-kappaB, known to act as an A(3)AR transcription factor. Interestingly, high A(3)AR expression levels were found in peripheral blood mononuclear cells (PBMCs) derived from tumor-bearing animals and cancer patients, reflecting receptor status in the tumors. A(3)AR agonists were found to induce tumor growth inhibition, both in vitro and in vivo, via modulation of the Wnt and the NF-kappaB signaling pathways. Taken together, A(3)ARs that are abundantly expressed in tumor cells may be targeted by specific A(3)AR agonists, leading to tumor growth inhibition. The unique characteristics of these A(3)AR agonists make them attractive as drug candidates.

[Orbital screwdriver injury in a toddler]. / Orbitale Schraubenzieherverletzung bei einem Kleinkind.

Presentation of a patient with an orbital intracranial penetrating screwdriver injury. The patient had been playing with the screwdriver at the time of the accident, he fell and the screwdriver penetrated his right orbit. Imaging revealed the position of the foreign body, which went from the medial orbital wall, extraconal and medial of the right internal carotid artery, through the sella turcica to the dorsum sellae. The patient had no intracranial hemorrhage. There was hardly any bleeding. The surgical removal of the screwdriver was carried out without complications.

Vessel Wall Enhancement in Unruptured Intracranial Aneurysms: An Indicator for Higher Risk of Rupture? High-Resolution MR Imaging and Correlated Histologic Findings.

BACKGROUND AND PURPOSE: Recent studies have suggested that wall enhancement of unruptured intracranial aneurysms in high-resolution MR imaging might serve as an imaging biomarker for higher risk of rupture. Histologic studies have revealed a possible association among inflammatory processes, degeneration, and destabilization of the aneurysm wall preceding rupture. Understanding the histologic condition underlying aneurysm wall enhancement could be an important step toward assessing the value of this method for risk stratification. We present our observations of aneurysm wall enhancement in MR vessel wall imaging and underlying histologic changes. MATERIALS AND METHODS: We reviewed records of patients with an unruptured middle cerebral artery aneurysm who underwent MR vessel wall imaging before aneurysm clipping. Contrast enhancement of the aneurysm wall was dichotomized into either none/faint or strong. Histologic analysis included myeloperoxidase stain for detection of inflammatory cell invasion and CD34 stain for assessment of neovascularization and vasa vasorum. RESULTS: Thirteen aneurysms were included. Five aneurysms showed strong wall enhancement. Among these, myeloperoxidase staining revealed inflammatory cell infiltration in 4. Three showed neovascularization. In 2 aneurysms, vasa vasorum were present. Seven aneurysms did not show wall enhancement; 1 had only mild enhancement. None of these bore evidence of inflammatory cell invasion or neovascularization, and they all lacked vasa vasorum. CONCLUSIONS: Wall enhancement in MR vessel wall imaging is associated with inflammatory cell invasion, neovascularization, and the presence of vasa vasorum. Enhancement does not occur when histologic signs of inflammation are absent. Our results support the hypothesis that MR vessel wall imaging could provide valuable information for risk stratification.

Reduced laser-evoked potential habituation detects abnormal central pain processing in painful radiculopathy patients.

BACKGROUND: Repetitive painful laser stimuli lead to physiological laser-evoked potential (LEP) habituation, measurable by a decrement of the N2/P2 amplitude. The time course of LEP-habituation is reduced in the capsaicin model for peripheral and central sensitization and in patients with migraine and fibromyalgia. In the present investigation, we aimed to assess the time course of LEP-habituation in a neuropathic pain syndrome, i.e. painful radiculopathy. METHODS: At the side of radiating pain, four blocks of 25 painful laser stimuli each were applied to the ventral thigh at the L3 dermatome in 27 patients with painful radiculopathy. Inclusion criteria were (1) at least one neurological finding of radiculopathy, (2) low back pain with radiation into the foot and (3) a positive one-sided compression of the L5 and/or S1 root in the MRI. The time course of LEP-habituation was compared to 20 healthy height and age matched controls. Signs of peripheral (heat hyperalgesia) and central sensitization (dynamic mechanical allodynia and hyperalgesia) at the affected L5 or S1 dermatome were assessed with quantitative sensory testing. RESULTS: Painful radiculopathy patients showed decreased LEP-habituation compared to controls. Patients with signs of central sensitization showed a more prominent LEP-habituation decrease within the radiculopathy patient group. CONCLUSIONS: Laser-evoked potential habituation is reduced in painful radiculopathy patients, which indicates an abnormal central pain processing. Central sensitization seems to be a major contributor to abnormal LEP habituation. The LEP habituation paradigm might be useful as a clinical tool to assess central pain processing alterations in nociceptive and neuropathic pain conditions. SIGNIFICANCE: Abnormal central pain processing in neuropathic pain conditions may be revealed with the laser-evoked potential habituation paradigm. In painful radiculopathy patients, LEP-habituation is reduced compared to healthy controls.

Laser-evoked potentials in painful radiculopathy.

OBJECTIVE: The aims of this exploratory study were (1) to develop a standardized objective electrophysiological technique with laser-evoked potentials to assess dorsal root damage quantitatively and (2) to correlate these LEP measures with clinical parameters and sensory abnormalities (QST) in the affected dermatome. METHODS: Thirty-eight patients with painful radiculopathy and 20 healthy subjects were investigated with LEP recorded from the affected dermatome and control areas as well as with quantitative sensory testing. Questionnaires evaluating severity and functionality were applied. RESULTS: On average, LEP amplitudes and latencies from the affected dermatomes did not differ from the contralateral control side. In patients with left L5 radiculopathy (more severely affected) the N2 latency was longer and the amplitudes reduced. CONCLUSIONS: The N2P2 amplitude correlated with pinprick evoked sensations in QST. The N2 latency from the affected dermatome correlates with pain intensity, chronicity, clinical severity and with a decrease of physical function. SIGNIFICANCE: An increase in N2-latency indicates a more pronounced nerve root damage, which is associated with a decrease of function and an increase of severity and pain. LEP amplitudes are associated with the functional status of the nociceptive system and may distinguish between degeneration of neuronal systems and central sensitization processes.

CD95 maintains stem cell-like and non-classical EMT programs in primary human glioblastoma cells.

Glioblastoma (GBM) is one of the most aggressive types of cancer with limited therapeutic options and unfavorable prognosis. Stemness and non-classical epithelial-to-mesenchymal transition (ncEMT) features underlie the switch from normal to neoplastic states as well as resistance of tumor clones to current therapies. Therefore, identification of ligand/receptor systems maintaining this privileged state is needed to devise efficient cancer therapies. In this study, we show that the expression of CD95 associates with stemness and EMT features in GBM tumors and cells and serves as a prognostic biomarker. CD95 expression increases in tumors and with tumor relapse as compared with non-tumor tissue. Recruitment of the activating PI3K subunit, p85, to CD95 death domain is required for maintenance of EMT-related transcripts. A combination of the current GBM therapy, temozolomide, with a CD95 inhibitor dramatically abrogates tumor sphere formation. This study molecularly dissects the role of CD95 in GBM cells and contributes the rational for CD95 inhibition as a GBM therapy.

Cerebral aneurysms associated with von Recklinghausen's neurofibromatosis: report of a case and review of the literature.

The authors report a case of an intracranial aneurysm associated with von Recklinghausen's neurofibromatosis. A 34-year-old woman presented with a history of headaches, unconsciousness and neck rigidity. Widespread cutaneous neurofibromas were found. Investigations revealed an aneurysm of the anterior communicating artery. The authors discuss this case and review the relevant literature.

Magnetic labeling of activated microglia in experimental gliomas.

Microglia, as intrinsic immunoeffector cells of the central nervous system (CNS), play a very sensitive, crucial role in the response to almost any brain pathology where they are activated to a phagocytic state. Based on the characteristic features of activated microglia, we investigated whether these cells can be visualized with magnetic resonance imaging (MRI) using ultrasmall superparamagnetic iron oxides (USPIOs). The hypothesis of this study was that MR microglia visualization could not only reveal the extent of the tumor, but also allow for assessing the status of immunologic defense. Using USPIOs in cell culture experiments and in a rat glioma model, we showed that microglia can be labeled magnetically. Labeled microglia are detected by confocal microscopy within and around tumors in a typical border-like pattern. Quantitative in vitro studies revealed that microglia internalize amounts of USPIOs that are significantly higher than those incorporated by tumor cells and astrocytes. Labeled microglia can be detected and quantified with MRI in cell phantoms, and the extent of the tumor can be seen in glioma-bearing rats in vivo. We conclude that magnetic labeling of microglia provides a potential tool for MRI of gliomas, which reflects tumor morphology precisely. Furthermore, the results suggest that MRI may yield functional data on the immunologic reaction of the CNS.

Glioblastoma multiforme versus solitary supratentorial brain metastasis: differentiation based on morphology and magnetic resonance signal characteristics.

PURPOSE: To evaluate the diagnostic potential of a multi-factor analysis of morphometric parameters and magnetic resonance (MR) signal characteristics of a mass and peritumoral area to distinguish solitary supratentorial metastasis from glioblastoma multiforme (GBM). MATERIALS AND METHODS: MR examinations of 51 patients with histologically proven GBM and 44 with a single supratentorial metastasis were evaluated. A large variety of morphologic criteria and MR signal characteristics in different sequences were analyzed. The data were subjected to logistic regression to investigate their ability to discriminate between GBM and cerebral metastasis. Receiver-operating characteristic (ROC) analysis was used to select an optimal cut-off point for prediction and to assess the predictive value in terms of sensitivity, specificity, and accuracy of the final model. RESULTS: The logistic regression analysis revealed that the ratio of the maximum diameter of the peritumoral area measured on T2-weighted images (d T2) to the maximum diameter of the enhancing mass area (d T1, post-contrast) is the only useful criterion to distinguish single supratentorial brain metastasis from GBM with a lower ratio favoring GBM (accuracy 68 %, sensitivity 84 % and specificity 45 %). The cut-off point for the ratio d T2/d T1 post-contrast was calculated as 2.35. CONCLUSION: Measurement of maximum diameters of the peritumoral area in relation to the enhancing mass can be evaluated easily in the clinical routine to discriminate GBM from solitary supratentorial metastasis with an accuracy comparable to that of advanced MRI techniques.

Transferrin-receptor-mediated iron accumulation controls proliferation and glutamate release in glioma cells.

Transferrin receptors (TfR) are overexpressed in brain tumors, but the pathological relevance has not been fully explored. Here, we show that TfR is an important downstream effector of ets transcription factors that promotes glioma proliferation and increases glioma-evoked neuronal death. TfR mediates iron accumulation and reactive oxygen formation and thereby enhanced proliferation in clonal human glioma lines, as shown by the following experiments: (1) downregulating TfR expression reduced proliferation in vitro and in vivo; (2) forced TfR expression in low-grade glioma accelerated proliferation to the level of high-grade glioma; (3) iron and oxidant chelators attenuated tumor proliferation in vitro and tumor size in vivo. TfR-induced oxidant accumulation modified cellular signaling by inactivating a protein tyrosine phosphatase (low-molecular-weight protein tyrosine phosphatase), activating mitogen-activated protein kinase and Akt and by inactivating p21/cdkn1a and pRB. Inactivation of these cell cycle regulators facilitated S-phase entry. Besides its effect on proliferation, TfR also boosted glutamate release, which caused N-methyl-D-aspartate-receptor-mediated reduction of neuron cell mass. Our results indicate that TfR promotes glioma progression by two mechanisms, an increase in proliferation rate and glutamate production, the latter mechanism providing space for the progressing tumor mass.

Embolization of indirect carotid-cavernous sinus fistulas using the superior ophthalmic vein approach.

OBJECTIVES: In indirect carotid-cavernous sinus fistulas (CCF), abnormal connections exist between tiny dural branches of the external and/or internal carotid system and the cavernous sinus. Usually this kind of fistula occurs spontaneously and is characterized by a low shunt volume. Alternative vascular approaches for embolization are required when standard interventional neuroradiological access via arterial or transfemoral venous routes is not feasible. PATIENTS AND METHODS: Two symptomatic patients with indirect CCFs are described. Transarterial and transfemoral venous approach was unsuccessful or resulted in incomplete occlusion of the CCF. Therefore, the superior ophthalmic vein (SOV) was surgically exposed and retrograde catheterized to allow the delivery of platinum coils to the fistula point via a microcatheter. RESULTS: Complete fistula obliteration was accompanied by recovery of the clinical symptoms. CONCLUSION: The surgical SOV approach might be sufficient when standard neuroradiological procedures do not succeed. The technique is safe and effective when performed by an interdisciplinary team.

GABA(A)-receptor expression in glioma cells is triggered by contact with neuronal cells.

The expression of functional GABA(A)-receptors in glioma cells correlates with low malignancy of tumours and cell lines from glioma lack these receptors. Here we show that contact with neurons induces the expression of functional GABA(A)-receptors. C6 and F98 glioma cell lines were labelled by recombinant expression of enhanced green fluorescent protein injected into rat brain and studied in acute slices after two to three weeks of tumour growth. The cells responded to GABA or the specific agonist, muscimol with a current typical for GABA(A)-receptors, as studied with the patch-clamp technique. To get insight into the mechanism of GABA(A) receptor induction, the C6 or F98 cells were co-cultured with neurons, astrocytes, oligodendrocytes and microglia. Glioma cells expressed functional GABA(A) receptors within 24 h only in cultures where physical contact to neurons occurred. Activation of GABA(A)-receptors in the co-cultures attenuated glioma cell metabolism while blockade of the receptors increased metabolism. We conclude that with this form of interaction, neurons can influence tumour behaviour in the brain.