Temporal lobe epilepsy due to meningoencephaloceles into the greater sphenoid wing: a consequence of idiopathic intracranial hypertension?

PURPOSE: Antero-inferior temporal lobe meningoencephaloceles are a rare, but increasingly recognized cause of drug-resistant temporal lobe epilepsy (TLE). In order to evaluate whether these lesions are related to idiopathic intracranial hypertension (IIH), we analyzed clinical and MRI findings of a cohort of patients undergoing presurgical work-up. METHODS: Seizure onset in the anterior temporal lobe was proven by EEG electrodes in 22 patients, and in 21 patients, anterior temporal lobectomy (mostly with sparing of the hippocampus) was performed. MRI signs of IIH (in particular empty sella) and the volumes of the ventricles and external CSF spaces were determined and related to the body mass index (BMI) and clinical outcome. RESULTS: Six of seven obese (BMI > 30 kg/m2) compared to four of 15 non-obese patients had partial empty or empty sella (p = 0.007). Bilateral lesions were found in all obese and 11 patients. Seizure freedom (Engel class 1A) was achieved in 12 of 21 patients (5 obese compared to 7 non-obese patients). BMI was related to the volume of the external CSF spaces (r = 0.467), and age at seizure onset was higher in obese patients. CONCLUSION: Roughly a third of patients with temporal lobe epilepsy due to antero-inferior meningoencephaloceles is obese and has MRI signs of idiopathic intracranial hypertension.

Supratentorial white matter blurring associated with voltage-gated potassium channel-complex limbic encephalitis.

INTRODUCTION: Limbic encephalitis (LE) associated with voltage-gated potassium channel-complex antibodies (VGKC-LE) is frequently non-paraneoplastic and associated with marked improvement following corticosteroid therapy. Mesial temporal lobe abnormalities are present in around 80 % of patients. If associated or preceded by faciobrachial dystonic seizures, basal ganglia signal changes may occur. In some patients, blurring of the supratentorial white matter on T2-weighted images (SWMB) may be seen. The purpose of this study was to evaluate the incidence of SWMB and whether it is specific for VGKC-LE. METHODS: Two experienced neuroradiologists independently evaluated signal abnormalities on FLAIR MRI in 79 patients with LE while unaware on the antibody type. RESULTS: SWMB was independently assessed as present in 10 of 36 (28 %) compared to 2 (5 %) of 43 non-VGKC patients (p = 0.009). It was not related to the presence of LGI1 or CASPR2 proteins of VGKC antibodies. MRI showed increased temporomesial FLAIR signal in 22 (61 %) VGKC compared to 14 (33 %) non-VGKC patients (p = 0.013), and extratemporomesial structures were affected in one VGKC (3 %) compared to 11 (26 %) non-VGKC patients (p = 0.005). CONCLUSION: SWMB is a newly described MRI sign rather specific for VGKC-LE.

Tractography of Association Fibers Associated with Language Processing.

INTRODUCTION: Several major association fiber tracts are known to be part of the language processing system. There is evidence that high angular diffusion-based MRI is able to separate these fascicles in a constant way. In this study, we wanted to proof this thesis using a novel whole brain "global tracking" approach and to test for possible lateralization. METHODS: Global tracking was performed in six healthy right-handed volunteers for the arcuate fascicle (AF), the medial longitudinal fascicle (MdLF), the inferior fronto-occipital fascicle (IFOF), and the inferior longitudinal fascicle (ILF). These fiber tracts were characterized quantitatively using the number of streamlines (SL) and the mean fractional anisotropy (FA). RESULTS: We were able to characterize the AF, the MdLF, the IFOF, and the ILF consistently in six healthy volunteers using global tracking. A left-sided dominance (LI > 0.2) for the AF was found in all participants. The MdLF showed a left-sided dominance in four participants (one female, three male). Regarding the FA, no lateralization (LI > 0.2) could be shown in any of the fascicles. CONCLUSION: Using a novel global tracking algorithm we confirmed that the courses of the primary language processing associated fascicles can consistently be differentiated. Additionally we were able to show a streamline-based left-sided lateralization in the AF of all right-handed healthy subjects.

Presurgical MR Imaging in Epilepsy.

Primary goal of magnetic resonance imaging in epilepsy patients is to detect epileptogenic lesions with small lesions best detectable on a 3D FLAIR SPACE sequence with 1 mm(3) voxels. Morphometric analysis of 3D T1-weighted data sets helps to find subtle lesions and may reveal the true extent of a lesion. In further presurgical work-up, language lateralization and spatial relationship of epileptogenic lesions to eloquent cortex and white matter tracts must be evaluated. With clear left lateralization language, fMRI is sufficient; in atypical lateralizations, Wada test and electrical stimulation mapping may be added. Primary motor cortex and corticospinal tract on one and visual cortex and optic radiation on the other side are displayed with fMRI and diffusion tensor tractography. For the corticospinal tract a "global" tracking algorithm, for the optic radiation including Meyer' loop, which may be damaged in anterior temporal lobe resections, a probabilistic algorithm is best suited.

[Pulmonary neuroendocrine neoplasms]. / Neuroendokrine Neoplasien der Lunge.

The pulmonary neuroendocrine neoplasms originate from the enterochromaffin cells which are diffusely distributed in the body. The incidence of these tumors has increased significantly in recent decades due to the available diagnostics. They make up about 1-2% of all lung tumors and 20-30% of all neuroendocrine neoplasms. The current WHO classification from 2004 divides them into typical carcinoids (TC), atypical carcinoids (AC), large cell neuroendocrine carcinomas (LCNEC) and small cell carcinomas (SCLC). The major neuroendocrine biomarkers are chromogranin A, synaptophysin and CD56. TC have a low mitotic rate of <2 mitoses/2mm(2) (10 HPF), whereas the mitotic rate of the AC is 2-10 mitoses/2 mm(2) (10 HPF). The Ki-67 staining is helpful to distinguish typical and atypical carcinoids from the highly malignant LCNEC and SCLC. Clinically, the patient presents usually with cough, hemoptysis or bronchial obstruction. The occurrence of a carcinoid or Cushing's syndrome and a tumor-associated acromegaly are rare. Surgical resection with radical lymph node dissection is the treatment of choice for achieving long-term survival. Endoscopic resection of the endobronchial tumor growth is a good alternative for inoperable endobronchially localized tumors. Peptide receptor radionuclide therapy (PRRT) is a promising treatment option for patients with metastatic or unresectable pulmonary neuroendocrine tumors. New targeted therapies using angiogenesis inhibitors, mTOR inhibitors, and tyrosine kinase inhibitors are being tested for their effectiveness in many previous studies. Typical carcinoid tumors metastasize less frequently than AC, the 5-year survival rate of patients with TC being over 90%. Patients with AC have a 5-year survival rate between 35% and 87%. The highly malignant LCNEC and SCLC, on the other hand, have a 5-year survival rate between 15% and 57%, and <5% respectively. The increasing number of therapeutic options and diagnostic procedures requires a multidisciplinary approach and decision-making in multidisciplinary tumor conferences to ensure a personalized treatment approach. Therefore patients with a neuroendocrine neoplasm of the lung should be treated in specialized centers.

MRI artefacts after Bonebridge implantation.

The new transcutaneous bone conduction implant (BCI) Bonebridge (BB, MED-EL) allows the skin to remain intact and therefore overcomes some issues related to percutaneous systems, such as skin reaction around the external screw and cosmetic complaints. According to manufacturer, BB is MRI conditional up to 1,5 Tesla (T). The artefact of the neurocranium after BB implantation is extensive as shown in the present report. This has to be taken into account when patients suffering conductive, mixed or single-sided hearing loss with candidacy for a BCI are counselled. In patients with comorbid intracranial tumour or other diseases of the brain that require imaging control scans with MRI percutaneous, BCI should be the implant of choice considering the very small artefact of the percutaneous screw in MRI.

[Expectoration of embolization coils 15 years after embolization of pulmonary arteriovenous malformations in a patient with hereditary hemorrhagic telangiectasia]. / Expektoration von Embolisationsspiralen 15 Jahre nach Embolisation pulmonaler arteriovenöser Malformationen bei hereditärer hämorrhagischer Teleangiektasie (M. Osler-Weber-Rendu).

Hereditary hemorrhagic telangiectasia can manifest itself with pulmonary arteriovenous malformations (pavm). A transcatheter coil embolization should be made to avoid complications and to close off relevant arteriovenous shunts. We report on a patient with expectoration of embolization coils 15 years after embolotherapy. In case of hemoptysis following embolotherapy with coils, even years after their placement one should consider coil migration into the pulmonary system, besides newly formed pavms, in the differential diagnosis and initiate contrast-CT of the thorax and bronchoscopy.

Superior neurologic recovery after 15 minutes of normothermic cardiac arrest using an extracorporeal life support system for optimized blood pressure and flow.

OBJECTIVE: Sudden cardiac arrest is one of the leading causes of death. Conventional CPR techniques after cardiac arrest provide circulation with reduced and varying blood flow and pressure. We hypothesize that using pressure- and flow-controlled reperfusion of the whole body improves neurological recovery and survival after 15 min of normothermic cardiac arrest. METHODS: Pigs were randomized in two experimental groups and exposed to 15 min of ventricular fibrillation (VF). After this period, the animals in the control group received conventional CPR with open chest compression (n=6), while circulation in the treatment group (n=6) was established with an extracorporeal life support system (ECLS) to control blood pressure and flow. Follow-up included the assessment of neurological recovery and magnetic resonance imaging (MRI) for up to 7 days. RESULTS: Five of the six animals in the control group died, one animal was resuscitated successfully. In the treatment group, 1/6 could not be separated from ECLS. Five out of the six pigs survived and were transferred to the animal facility. One animal was unable to walk and had to be sacrificed 30 hours after ECLS. The remaining 4 animals of the treatment group and the surviving pig from the control group showed complete neurological recovery. Brain MRI revealed no pathological changes. CONCLUSION: We were able to demonstrate a significant improvement in survival after 15 minutes of normothermic cardiac arrest. These results support our hypothesis that using an ECLS for pressure- and flow-controlled circulation after circulatory arrest is superior to conventional CPR.

Local and global fiber tractography in patients with epilepsy.

BACKGROUND AND PURPOSE: Fiber tractography is increasingly used in the preoperative evaluation of endangered fiber bundles. From a clinical point of view, an accurate and methodologically transparent procedure is desired. Our aim was to evaluate the recently described global tracking algorithm compared with other established methods, such as deterministic and probabilistic tractography. MATERIALS AND METHODS: Twenty patients, candidates for excision of epileptogenic lesions, were subjected to higher-angular resolution diffusion imaging-based fiber tractography. Seed points were created without manual bias, predominantly by FreeSurfer and voxel-based atlases. We focused on 2 important fiber bundles, namely the descending motor pathways and the optic radiation. Postoperatively, the accuracy of the predicted fiber route was controlled by structural MR imaging and by inflicted functional deficits. RESULTS: Among the 3 evaluated methods, global tracking was the only method capable of reconstructing the full extent of the descending motor pathways, including corticobulbar fibers from the area of face representation. Still, probabilistic tractography depicted the optic radiation better, especially the Meyer loop. The deterministic algorithm performed less adequately. CONCLUSIONS: The probabilistic method seems to be the best balance between computational time and effectiveness and seems to be the best choice in most cases, particularly for the optic radiation. If, however, a detailed depiction of the fiber anatomy is intended and tract crossings are implicated, then the computationally time-consuming global tracking should be preferred.

Prolonged cardiac arrest and resuscitation by extracorporeal life support: favourable outcome without preceding anticoagulation in an experimental setting.

State-of-the-art cardiopulmonary resuscitation (CPR) restores circulation with inconsistent blood-flow and pressure. Extracorporeal life support (ECLS) following CPR opens the opportunity for "controlled reperfusion". In animal experiments investigating CPR with ECLS, systemic anticoagulation before induced cardiac arrest is normal, but a major point of dispute, since preliminary heparinization in patients undergoing unwitnessed cardiac arrest is impossible. In this study, we investigated options for ECLS after an experimental 15 minutes normothermic cardiac arrest, without preceding anticoagulation, in pigs. Neurological recovery was assessed by a scoring system, electroencephalography and brain magnetic resonance imaging. Additionally, brain histology was performed on day seven after cardiac arrest. We demonstrated that preliminary heparin administration was not necessary for survival or neurological recovery in this setting. Heparin flushing of the cannulae seemed sufficient to avoid thrombus formation. These findings may ease the way to using ECLS in patients with sudden cardiac arrest.

Global tracking in human gliomas: a comparison with established tracking methods.

PURPOSE: Global tracking (GT) is a recently published fibre tractography (FT) method that takes simultaneously all fibres into account during their reconstruction. The purpose of this study was to compare this new method with fibre assignment by continuous tracking (FACT) and probabilistic tractography (PT) for the detection of the corticospinal tract (CST) in patients with gliomas. METHODS: Tractography of the CST was performed in 17 patients with eight low grade and nine anaplastic astrocytomas located in the motor cortex or the corticospinal tract. Diffusions metrics as fractional anisotropy (FA), mean (MD), axial (AD) and radial diffusivity (RD) were obtained. The methods were additionally applied on a physical phantom to assess their accuracy. RESULTS: PT was successful in all (100 %), GT in 16 (94 %) and FACT in 15 patients (88 %). The case where GT and FACT, both, missed the CST showed the highest AD and RD, whereas the one where FACT algorithm, alone, was not successfully showed the lowest AD and RD of the group. FA was reduced on the pathologic side (FApath 0.35 ± 0.16 (mean ± SD) versus FAcontralateral 0.51 ± 0.15, pcorr < 0.03). RD was increased on the pathologic side (RDpath 0.67 ± 0.29 × 10(-3) mm(2)/s versus RDcontralateral 0.46 ± 0.08 × 10(-3) mm(2)/s, pcorr < 0.03). In the phantom measurement, only GT did not detect false positive fibres at fibre crossings. CONCLUSION: PT performed well even in areas of increased diffusivities indicating a severe oedema or disintegration of tissue. FACT was also susceptible to a decrease of diffusivities and to a susceptibility artefact, where GT was robust.

Bevacizumab as salvage therapy for progressive brain stem gliomas.

OBJECTIVE: There is no standard of care for patients with progredient brain stem gliomas. Therefore, we report about clinical, radiological and metabolic response to anti-angiogenic treatment with bevacizumab in a series of 3 patients with gliomas involving the brain stem. PATIENTS AND METHODS: Three patients with histologically confirmed gliomas involving the brain stem were treated with bevacizumab for tumor progression. The clinical data, histopathological findings as well as MRI and PET follow up examinations during bevacizumab therapy were retrospectively analyzed. RESULTS: The histopathological diagnosis revealed an anaplastic astrocytoma WHO grade III in two patients and an astrocytoma WHO grade II in 1 patients with clinical and neuroradiological signs of malignization. One patient is still progression-free 97 weeks after initiation of bevacizumab therapy. Mean progression-free survival and overall survival for the other two patients after initiation of bevacizumab therapy was 34.5 weeks and 43.5 weeks. During bevacizumab therapy mean KPS improved from 60 to 80 and mean dosage of daily dexamathasone was reduced from 7.3 mg to 1.3 mg. MRI showed a decrease of T2 weighted hyperintense lesions in all patients and a decrease of contrast enhancement in two patients. (18)F-FET-PET showed a decrease of tracer uptake in all cases (mean maximum decrease: 25%). CONCLUSION: In this series treatment of progressive gliomas involving the brain stem with bevacizumab resulted in an improved clinical condition of the patients as well as a reduction of the T2 weighted lesions and reduced amino acid uptake in the tumor area. It therefore may represent a therapeutic salvage option for this type of tumor.

Impairment of lysosomal integrity by B10, a glycosylated derivative of betulinic acid, leads to lysosomal cell death and converts autophagy into a detrimental process.

In this study, we report a novel mechanism of action for a cytotoxic derivative of betulinic acid (BA). B10 is a semi-synthetic glycosylated derivative of BA selected for its enhanced cytotoxic activity. Interestingly, although B10 induces apoptosis, caspase-3 downregulation incompletely prevents B10-induced cell death, Bcl-2 overexpression fails to protect cells and DNA fragmentation rates do not reflect cell death rates in contrast to cytoplasmic membrane permeabilization. These results implicate that apoptotic and non-apoptotic cell death coexist upon B10 treatment. Unexpectedly, we found that B10 induces autophagy and also abrogates the autophagic flux. B10 destabilizes lysosomes as shown by Lysotracker Red staining and by cathepsin Z and B release from lysosomes into the cytoplasm. Consistently, the cathepsin inhibitor Ca074Me significantly decreases B10-induced cell death, further supporting the fact that the release of lysosomal enzymes contributes to B10-triggered cell death. Downregulation of ATG7, ATG5 or BECN1 by RNAi significantly decreases caspase-3 activation, lysosomal permeabilization and cell death. Thus, by concomitant induction of autophagy and inhibition of the autophagic flux, B10 turns autophagy into a cell death mechanism. These findings have important implications for the therapeutic exploitation of BA derivatives, particularly in apoptosis-resistant cancers.

Histone deacetylase inhibitors prime medulloblastoma cells for chemotherapy-induced apoptosis by enhancing p53-dependent Bax activation.

Despite aggressive therapies, the prognosis of children with high-risk medulloblastoma is still poor, thus underscoring the need to develop novel treatment strategies. Here, we report that histone deacetylase inhibitors (HDACI), that is, MS-275, valproic acid or SAHA, provide a novel strategy for sensitization of medulloblastoma to DNA-damaging drugs such as Doxorubicin, VP16 and Cisplatin by promoting p53-dependent, mitochondrial apoptosis. Mechanistic studies reveal that single-agent treatment with MS-275 causes acetylation of the non-histone protein Ku70, an event reported to release Bax from Ku70, whereas DNA-damaging drugs trigger p53 acetylation and accumulation. Combined treatment with MS-275 and Doxorubicin or VP16 cooperates to promote binding of p53 to Bax and p53-dependent Bax activation, resulting in enhanced loss of mitochondrial membrane potential, cytochrome c release and caspase-dependent apoptosis. Overexpression of Bcl-2 almost completely abolishes the MS-275-mediated chemosensitization, underlining the importance of the mitochondrial pathway for inducing apoptosis. Also, MS-275 cooperates with chemotherapeutics to inhibit long-term clonogenic survival. Most importantly, MS-275 increases chemotherapeutic drug-induced apoptosis in primary medulloblastoma samples, and cooperates with Doxorubicin to suppress medulloblastoma growth in an in vivo model, which underscores the clinical relevance of the findings. Thus, HDACI such as MS-275 present a promising approach for chemosensitization of medulloblastoma by enhancing mitochondrial apoptosis in a p53-dependent manner. These findings have important clinical implications for the design of experimental treatment protocols for medulloblastoma.