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.

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.

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.

Epilepsy surgery in patients with multiple cerebral cavernous malformations.

PURPOSE: Cerebral cavernous malformations (CCMs) are frequently associated with intractable epilepsy. Whereas surgery indication in single CCMs is clear, data regarding the efficacy of epilepsy surgery in patients with multiple CCMs are scarce. We sought to clarify diagnostic requirements and postoperative outcome in patients with multiple CCMs and refractory epilepsy. METHODS: Retrospective analysis of clinical records of hospitalized patients who underwent comprehensive diagnostic work-up including long-term video-EEG monitoring. RESULTS: From a total of 63 consecutive patients with CCMs and medically refractory epilepsy, 11 (17%) had multiple CCMs and underwent epilepsy surgery. There were three females and eight males. Mean age at epilepsy onset was 28.3 years (S.D. 12.3), and at epilepsy surgery, 40.7 years (S.D. 10.3). On average, each patient had 3.7 (S.D. 2.2) supratentorial CCMs. In all cases we identified only one epileptogenic zone. The epileptogenicity was higher for the CCMs located within the temporal lobe. At 2 years follow-up, the outcome according to the Engel classification was Ia (seizure-free) in nine patients (81.8%) and IIb (rare seizures) and IVc (worsening) in two patients, respectively. In one patient, a dual pathology was present and, in another case, de novo appearance of CCMs was demonstrated. CONCLUSIONS: Our results show that postoperative outcome in patients with multiple CCMs can be as good as in those with single malformations if proper presurgical identification of the epileptogenic CCMs is done. The possibility of the novo appearance of CCMs or dual pathology may occur and may affect long-term outcome negatively.

Progressive multifocal leukoencephalopathy: value of diffusion-weighted and contrast-enhanced magnetic resonance imaging for diagnosis and treatment control.

Progressive multifocal leukoencephalopathy (PML) is caused by the replication of JC virus in oligodendrocytes of immunocompromised patients. Diagnosis usually relies on the polymerase chain reaction (PCR)-based demonstration of JC virus DNA in the cerebrospinal fluid. As previous reports have suggested that some patients may benefit from antiviral therapy, non-invasive early diagnosis is highly desirable. Repetitive magnetic resonance imaging (MRI) examinations (two to nine) were obtained in seven patients (aged 40-67 years, six males, one female) with classical clinical and imaging findings of PML. Five patients had underlying hematological disorders and two acquired immune deficiency syndrome. PCR of the cerebrospinal fluid (CSF) specimen was positive for JC virus DNA in six patients. MRI sequences included T2-, T1- and diffusion-weighted (DW) images in all patients and diffusion-tensor imaging (DTI) in four cases. DTI was once performed at 3T, in the remaining patients at 1.5T. All patients received antiviral treatment with cidofovir in addition to the treatment of the underlying disorder. MRI showed areas of T2 hyperintensity with involvement of the subcortical U-fibers and restricted diffusion in all patients. Areas of diffusion abnormality correlated with disease progress. Contrast enhancement was encountered once after successful treatment and heralded clinical remission with virus elimination from the CSF. Hence, MRI including DW and contrast-enhanced images may be used to evaluate disease activity. Contrast enhancement may indicate an inflammatory response and thus herald immunologic virus elimination.

MRI and proton MR spectroscopy in acute disseminated encephalomyelitis.

INTRODUCTION: Acute disseminated encephalomyelitis (ADEM) is one of a group of demyelinating disorders of the central nervous system (CNS). It is said to be attributed to an overshooting immunologic response following an infection or vaccination. The clinical course and type of manifestation is heterogeneous. The early application of corticosteroids has been shown to be beneficial to outcome; thus, an early diagnosis is highly desirable. METHODS: The potential diagnostic value of advanced MR techniques such as proton MR spectroscopy and diffusion-weighted imaging (DWI) was investigated in two paediatric patients with ADEM, one of whom had a remitting and relapsing clinical course and presented with additional cranial nerve involvement. Proton MR spectroscopy revealed typical signs of acute demyelination, such as increased macromolecules, not found in other forms of non-necrotising pathology. CONCLUSION: The addition of proton MR spectroscopy and DWI adds to the diagnostic power of MRI in the setting of post-infectious demyelinating disorders of the CNS or ADEM and may obviate the need for biopsy.

Modern MRI tools for the characterization of acute demyelinating lesions: value of chemical shift and diffusion-weighted imaging.

Acute demyelinating lesions occur in various inflammatory disorders of the CNS. Apart from multiple sclerosis, most cases can be attributed to an overshooting immunological response to infectious agents called acute disseminated encephalomyelitis (ADEM). ADEM, which is mostly characterized by a monophasic course, has a multiphasic variant (MDEM). The early application of corticosteroids has been shown to be beneficial for the outcome; thus, an early diagnosis is highly desirable. Furthermore, the differential diagnosis ruling out neoplastic disorders may be difficult using conventional MRI alone. The potential diagnostic value of advanced MR techniques such as chemical shift imaging (CSI) and diffusion-weighted imaging (DWI) was investigated in a patient with MDEM, who had a new lesion in continuity with the initial disease manifestation. CSI was performed at 1.5 T with a long echo time of 135 ms for the evaluation of N-acetyl-aspartate (NAA) and choline (Cho) and with short TE of 30 ms for macromolecules (mm) and myo-Inositol (mI). DWI was performed using a single-shot isotropic EPI sequence. Whereas acute and chronic areas of demyelination were neither distinguishable on T2- nor on contrast-enhanced T1-weighted images, CSI and DWI revealed different metabolite concentrations and diffusion characteristics within the composite lesion, clearly separating acute from chronic areas of demyelination. In conclusion, the addition of CSI and DWI may add to the diagnostic power of MRI in the setting of demyelinating disorders by identifying areas of acute and chronic demyelination, even in the absence of contrast enhancement.