When should we test for voltage-gated potassium channel complex antibodies? A retrospective case control study.

Patients with voltage-gated potassium channel (VGKC)-complex antibodies are increasingly recognized as having central, peripheral or combined phenotypes. With increasing awareness, more patients are tested and the clinical spectrum is expanding. Consequently, clinicians may be uncertain as to which patients should or should not be tested. Previous studies have identified common clinical features, but none has looked at the usefulness of these in predicting seropositive disease. We conducted a case-control study of patients tested for VGKC-complex antibodies over 10years at a regional tertiary neurology centre determining which clinical/biochemical features were associated with antibody-positive disease. We found a marked increase in the numbers tested, although the percentage positive remained low. Antibody titre was highest in central disease (p<0.001). Time from presentation to testing was shorter in those with VGKC-disease (p=0.01). Seizures were present in 11 (69%) of those with VGKC-disease versus three (18%) without (odds ratio [OR] 10.3, 95% confidence interval [CI]: 2.0-52.7, p=0.005). There was an inverse correlation between the antibody titre and serum sodium. A multivariate model selected seizures and hyponatraemia as predictive of VGKC disease (sensitivity 75% and specificity 82%); faciobrachial dystonic movements were specific but insensitive. Interestingly serum alkaline phosphatase was higher in those with VGKC-disease (p=0.016) and highest in those with peripheral disease (p=0.015). An ALP>70u/L was strongly associated with antibody positivity (OR 4.11 95% CI: 1.43-11.8, p=0.007) with a sensitivity of 74.2%. The presence of seizures, faciobrachial movements, and hyponatraemia should raise suspicion of VGKC-disease; alkaline phosphatase may represent a novel biomarker, particularly in those with peripheral disease.

The role of the corpus callosum in seizure spread: MRI lesion mapping in oligodendrogliomas.

BACKGROUND: Some patients with oligodendrogliomas have generalized tonic-clonic seizures (GTCS) while others have only partial seizures (PS). We investigated the relationship between tumour localization and seizure generalization using quantitative lesion mapping on magnetic resonance images. METHODS: Twenty one patients with histologically proven oligodendrogliomas and GTCS (n=11) or PS (n=10) were studied. Data were acquired on a 3 Tesla MRI System. We performed lesion mapping techniques to compare the spatial distribution of oligodendrogliomas between patient groups, and quantitatively determined the extent to which lesions intersected each probabilistic regions-of-interest, including the cerebral lobes, thalamus, striatum, and genu of the corpus callosum. RESULTS: In patients experiencing GTCS, the greatest lesion load was observed in mesial frontal regions, including cortex connected to the genu. In contrast, the greatest lesion load in patients experiencing PS was observed more caudo-laterally in orbitofrontal and temporal lobes, but typically sparing cortex connected to the genu. The number of lesion intersections with genu region of interest was significantly greater in patients experiencing GTCS relative to patients with PS (p=0.03). There were no significant differences between patient groups with respect to lesion intersection with the individual cerebral lobes, thalamus and striatum, or with respect to overall oligodendroglioma size. CONCLUSION: Our data suggest that the genu of the corpus callosum may be a major pathway for seizure generalization in patients with oligodendrogliomas.

Cerebellopontine angle oligodendroglioma in a child: first case report.

The reported incidence of oligodendrogliomas in the paediatric population is less than 1 %. The posterior fossa is a rare location, with the vast majority arising in the cerebral hemispheres. We report the first paediatric case of a WHO grade II oligodendroglioma arising in the cerebellopontine angle (CPA). CPA oligodendrogliomas in children appear to behave aggressively and adjuvant therapy must be considered early; especially when complete resection cannot be achieved.

Apparatus for dimensional characterization of fused silica fibers for the suspensions of advanced gravitational wave detectors.

Detection of gravitational waves from astrophysical sources remains one of the most challenging problems faced by experimental physicists. A significant limit to the sensitivity of future long-baseline interferometric gravitational wave detectors is thermal displacement noise of the test mass mirrors and their suspensions. Suspension thermal noise results from mechanical dissipation in the fused silica suspension fibers suspending the test mass mirrors and is therefore an important noise source at operating frequencies between ∼10 and 30 Hz. This dissipation occurs due to a combination of thermoelastic damping, surface and bulk losses. Its effects can be reduced by optimizing the thermoelastic and surface loss, and these parameters are a function of the cross sectional dimensions of the fiber along its length. This paper presents a new apparatus capable of high resolution measurements of the cross sectional dimensions of suspension fibers of both rectangular and circular cross section, suitable for use in advanced detector mirror suspensions.

Invited article: CO2 laser production of fused silica fibers for use in interferometric gravitational wave detector mirror suspensions.

In 2000 the first mirror suspensions to use a quasi-monolithic final stage were installed at the GEO600 detector site outside Hannover, pioneering the use of fused silica suspension fibers in long baseline interferometric detectors to reduce suspension thermal noise. Since that time, development of the production methods of fused silica fibers has continued. We present here a review of a novel CO(2) laser-based fiber pulling machine developed for the production of fused silica suspensions for the next generation of interferometric gravitational wave detectors and for use in experiments requiring low thermal noise suspensions. We discuss tolerances, strengths, and thermal noise performance requirements for the next generation of gravitational wave detectors. Measurements made on fibers produced using this machine show a 0.8% variation in vertical stiffness and 0.05% tolerance on length, with average strengths exceeding 4 GPa, and mechanical dissipation which meets the requirements for Advanced LIGO thermal noise performance.

Biology, genetics and imaging of glial cell tumours.

Despite advances in therapy, gliomas remain associated with poor prognosis. Clinical advances will be achieved through molecularly targeted biological therapies, for which knowledge of molecular genetic and gene expression characteristics in relation to histopathology and in vivo imaging are essential. Recent research supports the molecular classification of gliomas based on genetic alterations or gene expression profiles, and imaging data supports the concept that molecular subtypes of glioma may be distinguished through non-invasive anatomical, physiological and metabolic imaging techniques, suggesting differences in the baseline biology of genetic subtypes of infiltrating glioma. Furthermore, MRI signatures are now being associated with complex gene expression profiles and cellular signalling pathways through genome-wide microarray studies using samples obtained by image guidance which may be co-registered with clinical imaging. In this review we describe the pathobiology, molecular pathogenesis, stem cells and imaging characteristics of gliomas with emphasis on astrocytomas and oligodendroglial neoplasms.

Brain biopsy in the management of neurology patients.

BACKGROUND AND METHODS: To evaluate the value of brain biopsy for neurology patients in our unit, we conducted a retrospective audit of neurology patients referred for brain biopsies for non-neoplastic disease from 1993 to 2007. RESULTS: 64 patients [median (range) age 51 (16-74) years] were included. The clinical presentation was diffuse encephalopathy for 40 patients, focal for 13 and multifocal for 11. The biopsy was diagnostic in 34 patients, abnormal but non-diagnostic in 21 and normal in 9. There was a statistically significant association between clinical presentation and biopsy result (p = 0.004); diagnostic biopsies were more common in patients with focal or multifocal clinical presentations. Twenty patients (31%) had alterations of management as a result of their brain biopsy, comprising specific treatment (11 patients) or prognosis/diagnosis of untreatable conditions (9 patients). Diagnoses of treatable conditions included Whipple's disease, tuberculoma, progressive multifocal leukoencephalopathy, and neurosarcoidosis. Five patients (7.8%) had complications. CONCLUSIONS: Brain biopsy is useful and relatively safe in the management of neurology patients, with a diagnostic yield of 53% in our series; some led to significant changes in management, including treatment of infections. Patients with focal or multifocal presentation are more likely to yield a diagnostic biopsy result.

Role of hepcidin in murine brain iron metabolism.

Brain iron homeostasis is maintained by a balance of both iron uptake and release, and accumulating evidence has revealed that brain iron concentrations increase with aging. Hepcidin, an iron regulatory hormone produced by hepatocytes in response to inflammatory stimuli, iron, and hypoxia, has been shown to be the long-sought hormone responsible for the regulation of body iron balance and recycling in mammals. In this study, we report that hepcidin is widely expressed in the murine brain. In cerebral cortex, hippocampus and striatum, hepcidin mRNA levels increased with aging. Injection of hepcidin into the lateral cerebral ventricle resulted in decreased Fpn1 protein levels in cerebral cortex, hippocampus, and striatum. Additionally, treatment of primary cultured neurons with hepcidin caused decreased neuronal iron release and Fpn1 protein levels. Together, our data provide further evidence that hepcidin may be involved in the regulation of brain iron metabolism.

Extent of MGMT promoter methylation correlates with outcome in glioblastomas given temozolomide and radiotherapy.

BACKGROUND: Epigenetic silencing of O(6)-methylguanine-DNA-methyltransferase (MGMT) by promoter methylation is associated with improved survival in glioblastomas treated with alkylating agents. In this study, we investigated MGMT promoter methylation in glioblastomas treated with temozolomide and radiotherapy in a single UK treatment centre. METHODS: Quantitative methylation data at individual CpG sites were obtained by pyrosequencing for 109 glioblastomas. RESULTS: Median overall survival (OS) was 12.4 months with 2-year survival of 17.9%. Pyrosequencing data were reproducible with archival samples yielding data for all glioblastomas. Variation in methylation patterns of discrete CpG sites and intratumoral methylation heterogeneity were observed. A total of 58 out of 109 glioblastomas showed average methylation >non-neoplastic brain in at least one clinical sample; 86% had homogeneous methylation status in multiple samples. Methylation was an independent prognostic factor associated with prolonged progression-free survival (PFS) and OS. Cases with methylation more than 35% had the longest survival (median PFS 19.2; OS 26.2 months, 2-year survival of 59.7%). Significant differences in PFS were seen between those with intermediate or high methylation and unmethylated cases, whereas cases with low, intermediate or high methylation all showed significantly different OS. CONCLUSIONS: These data indicate that MGMT methylation is prognostically significant in glioblastomas given chemoradiotherapy in the routine clinic; furthermore, the extent of methylation may be used to provide additional prognostic stratification.

Patterns of antiepileptic drug overdose differ between men and women: admissions to the Edinburgh Poisons Unit, 2000-2007.

BACKGROUND AND AIMS: Antiepileptic drugs are increasingly used in patients with psychiatric disorders who are at increased risk of self-harm. This might increase the likelihood that these agents are used as a means of overdose. This study was designed to examine the rate of occurrence of antiepileptic drug overdose between 2000 and 2007. METHODS: A retrospective observational study examined patterns of antiepileptic drug overdose in patients admitted to the Edinburgh Poisons Unit, and compared prescription data for the corresponding region. Data were compared using chi-square trend tests. RESULTS: There were 18 010 admissions to the Toxicology Unit, and 613 patients ingested at least one antiepileptic drug (3.4%). The most frequently implicated were carbamazepine, sodium valproate, phenytoin and lamotrigine, which corresponded with those most commonly prescribed. Women were more likely to ingest lamotrigine than men (P < 0.0001), and less likely to ingest sodium valproate (P = 0.0234). Patients that ingested antiepileptic drugs were more likely to be admitted to hospital for >1 day (22% vs. 8%, P < 0.0001) and need transfer to a psychiatric facility (14% vs. 7%, P < 0.0001). CONCLUSIONS: Patients that ingested antiepileptic drugs required more intensive medical and psychiatric intervention compared to ingestion of other agents. Significant gender differences were noted in the specific antiepileptic drug ingested. Further work is required to establish whether this discrepancy may be explained by gender-based prescribing practices.

Band-like intracranial calcification with simplified gyration and polymicrogyria: a distinct "pseudo-TORCH" phenotype.

The combination of intracranial calcification and polymicrogyria is usually seen in the context of intrauterine infection, most frequently due to cytomegalovirus. Rare familial occurrences have been reported. We describe five patients-two male-female sibling pairs, one pair born to consanguineous parents, and an unrelated female-with a distinct pattern of band-like intracranial calcification associated with simplified gyration and polymicrogyria. Clinical features include severe post-natal microcephaly, seizures and profound developmental arrest. Testing for infectious agents was negative. We consider that these children have the same recognizable "pseudo-TORCH" phenotype inherited as an autosomal recessive trait.

Low grade astrocytoma of the pituitary stalk.

A case of low grade astrocytoma (WHO grade II) localised in the pituitary stalk is reported in a 46 year old female who presented with central diabetes insipidus. Six-monthly magnetic resonance imaging was use to determine the progression of the lesion. The patient had a stereotactic biopsy of the lesion 18 months after the initial presentation. The diagnosis was established with the aid of immunohistochemistry. We emphasize the importance of MRI before initiating therapy to evaluate the pituitary stalk lesion and the effectiveness of stereotactic biopsy in securing tissue diagnosis without additional deficit.

Th1/Th2 cytokine imbalance in meningioma, anaplastic astrocytoma and glioblastoma multiforme patients.

The balance between Th1 and Th2 cytokines is thought to be an important factor in terms of tumour prognosis. Serum samples from 61 newly diagnosed patients with brain tumours and 50 age- and sex-matched non-tumour controls were analysed by ELISA for circulating levels of interleukin-12 (IL-12p70 and p40) and interleukin-10 (IL-10); pivotal Th1 and Th2 cytokines, respectively. Patients were divided into various groups depending on their histological diagnosis: meningioma (n=11), anaplastic astrocytoma (n=4) and glioblastoma multiforme (GBM; n=46). Significant reduction in serum IL-12 was seen in all groups as compared with the controls: meningioma, p=0.03; anaplastic astrocytoma, p<0.001; and GBM, p<0.001. Conversely, serum IL-10 was significantly increased in anaplastic astrocytoma, p=0.02, and GBM, p=0.03. The changes in the serum cytokines were not caused by the effects of steroids, as sequential analysis of patients pre- and post-steroid treatment commencement showed no difference. This study shows that patients with advanced primary intracranial malignancies have decreased circulating IL-12 and increased circulating IL-10, demonstrating that brain tumours have a major systemic effect on the immune system.

Gab1 signaling is regulated by EGF receptor sorting in early endosomes.

Although combinatorial signaling through the ErbB network is implicated in certain types of human cancer, the specifics of how particular receptors contribute to the transformed phenotype are not well understood. The goal of this study was to identify epidermal growth factor (EGF) receptor-dependent cell signaling abnormalities specifically associated with mutations in a previously described 679-LL lysosomal sorting signal, which restrict ligand-dependent receptor downregulation by promoting recycling. Importantly, the 679-LL signal is not conserved in any of the other members of the ErbB receptor family suggesting its physiological function may be tightly regulated during EGF receptor-dependent signaling. Our data indicate that cells expressing receptors with an inactive 679-AA signal are rapidly transported to Rab4+ early endosomes after they are internalized in contrast to wild-type receptors that are localized to early endocytic antigen 1 (EEA1)+ early endosomes. Divergent trafficking in early endosomes is associated with prolonged activation of p44/42 mitogen-activated protein kinases (MAPK) but not Akt. Gab1 appears to be the critical signaling molecule facilitating prolonged MAPK signaling, and activated Gab1 is recruited to early endosomes in 679-AA receptor-expressing cells. Activated Gab1 is also recruited to early endosomes in breast cancer cells characterized by high levels of EGF receptor-ErbB2 heterodimers, suggesting 679-AA expressing cells recapitulate certain aspects of EGF receptor signaling and transformation by activated ErbB2. Phosphatidylinositol 3-kinase (PI3K)-dependent membrane translocation known to be important for maintaining Gab1 activity in other settings was dispensable. We conclude that 679-LL has dual functions in EGF receptor trafficking and threshold signaling through a subset of signaling molecules including p44/42 MAPK and Gab1.

Thermal noise from optical coatings in gravitational wave detectors.

Gravitational waves are a prediction of Einstein's general theory of relativity. These waves are created by massive objects, like neutron stars or black holes, oscillating at speeds appreciable to the speed of light. The detectable effect on the Earth of these waves is extremely small, however, creating strains of the order of 10(-21). There are a number of basic physics experiments around the world designed to detect these waves by using interferometers with very long arms, up to 4 km in length. The next-generation interferometers are currently being designed, and the thermal noise in the mirrors will set the sensitivity over much of the usable bandwidth. Thermal noise arising from mechanical loss in the optical coatings put on the mirrors will be a significant source of noise. Achieving higher sensitivity through lower mechanical loss coatings, while preserving the crucial optical and thermal properties, is an area of active research right now.

Qualitative assessment of patient experiences related to extended pelvic resection for rectal cancer.

BACKGROUND: Patients with locally advanced rectal cancer (LARC) and locally recurrent rectal cancer (LRRC) represent a complex management challenge. While there is potential for cure in a subset of patients, the cost in terms of morbidity can be high. Few descriptions of the physical, psychological, social, and emotional experiences of these patients exist. METHODS: Face-to-face interviews were completed with ten LARC and LRRC patients treated with multimodal therapy that included surgery. Patient opinions and experiences were explored in depth until information redundancy and common themes were delineated using qualitative research methods. Clinical information was obtained from the database. RESULTS: Nine of the ten patients were male, seven had LARC, and the median age was 71. Six themes were identified from the patient interviews. Themes reflected patients' highly focused desire to seek wellness and cure, but also revealed misunderstanding of their disease biology, probability of cure, therapeutic options, and treatment morbidity. CONCLUSIONS: Patient experiences confirm that this is challenging treatment to complete, and that patient understanding of pre-operative information is incomplete. Our findings underscore the need for a multidisciplinary approach when managing this patient population, with emphasis on both supportive care needs and the technically skilled delivery of surgery, chemotherapy, and radiotherapy.

[Use of telepathology to provide rapid diagnosis of neurosurgical specimens]. / Intérêt de la télépathologie dans le diagnostic rapide des spécimens neurochirurgicaux.

To determine whether still digital images of neurosurgical specimens sent by e-mail are an effective and safe way of obtaining an emergency pathological diagnosis, representative images from 48 neurosurgical smear specimens were digitized, compressed and sent by electronic mail to our consultant neuropathologist with relevant clinical and radiological information. The time to select, digitize, compress and send the images for each case was recorded. Comparison was made between diagnosis made from digital images (DI) and historical smear (HS) using the original permanent section (PS) diagnosis as the gold standard. A diagnosis of normal vs. abnormal, neoplastic vs. non-neoplastic, primary vs. secondary and tumor grade was made in each case. The mean time for selection and digitalization of each case was 9.51 minutes. The number of correct pathological diagnosis was 41/48 using DI and 48/48 using HS, giving an accuracy rate of 85.4% and 100% respectively. DI was 100% sensitive in recognizing neoplastic tissue but only 98% specific. Most inaccuracies were in grading and caused by problems with field selection and familiarity with the technique. We conclude that static digital images are reliable and safe method of interpreting tissue during neurosurgical procedures. This corresponds with the findings of previous studies.

Paraganglioma of the filum terminale.

Paraganglioma of the filum terminale is rare. The authors report a case of paraganglioma of the filum terminale presenting with paraparesis on a background of spastic quadriparesis. The clinical presentation, radiological findings and current literature are presented.

The immunohistochemical localisation of somatostatin receptors 1, 2, 3, and 5 in acoustic neuromas.

AIMS: Acoustic neuroma is a benign tumour, which develops through an overproliferation of Schwann cells along the vestibular nerve. Somatostatin is a naturally occurring peptide, which exerts antiproliferative and antiangiogenic effects via five membrane bound receptor subtypes. The aim of this study was to determine whether somatostatin receptor subtypes (SSTRs) 1, 2, 3, and 5 are present in acoustic neuromas. METHODS: The expression of SSTRs 1, 2, 3, and 5 was studied in both the Schwann cells and blood vessels of eight acoustic neuroma specimens, by means of immunohistochemistry using novel rabbit polyclonal antibodies raised against human SSTR 1, 2, and 5 subtype specific peptides, and a commercial anti-SSTR3 antibody. RESULTS: SSTR2 was the most prevalent subtype in Schwann cells (seven of eight), with intermediate expression of SSTR3 (six of eight), and lower expression of SSTRs 1 and 5 (four of eight and five of eight, respectively). There was ubiquitous vascular expression of SSTR2, with no evidence of SSTR 1, 3, or 5 expression in blood vessels. CONCLUSION: SSTRs 1, 2, 3, and 5 are differentially expressed in acoustic neuromas. Somatostatin analogues may have a therapeutic role in the management of this rare and challenging condition.

Epidemiology of central nervous system tumors in children and young adults (0-29 years), Yorkshire, United Kingdom.

The authors describe the incidence and survival of 480 patients diagnosed under 30 years with a CNS tumor in Yorkshire, UK, between 1990 and 2001. The effect on survival from deprivation and other prognostic factors was examined. Young adults (aged 15-29) were significantly less likely to develop CNS tumors than children (p = .001), largely because of an excess of medulloblastoma and ependymoma in the pediatric age range. No significant temporal trends in incidence were present apart from young adults with "other CNS" tumors showing an average annual increase of 10.7% (95% CI 1.3-21.0%; p = .03). Young adults had significantly lower survival rates than children (hazard ratio = 1.52, 95% CI 1.10-2.10). The highest risk of death was observed for patients from the most affluent areas. The overall burden of CNS tumors appears to be relatively constant, but the significantly poorer survival for young people needs further rapid investigation.