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Neuro-Oncology
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Jassam, S. A., Maherally, Z., Smith, J. R., Ashkan, K., Roncaroli, F., Fillmore, H. L., Pilkington, G. J., 2015-10-16 08:28:36 AM
Background
CD15, which is overexpressed on various cancers, has been reported as a cell adhesion molecule that plays a key role in non-CNS metastasis. However, the role of CD15 in brain metastasis is largely unexplored. This study provides a better understanding of CD15/CD62E interaction, enhanced by tumor necrosis factor-α (TNF-α), and its correlation with brain metastasis in non–small cell lung cancer (NSCLC).
Methods
CD15 and E-selectin (CD62E) expression was demonstrated in both human primary and metastatic NSCLC cells using flow cytometry, immunofluorescence, and Western blotting. The role of CD15 was investigated using an adhesion assay under static and physiological flow live-cell conditions. Human tissue sections were examined using immunohistochemistry.
Results
CD15, which was weakly expressed on hCMEC/D3 human brain endothelial cells, was expressed at high levels on metastatic NSCLC cells (NCI-H1299, SEBTA-001, and SEBTA-005) and at lower levels on primary NSCLC (COR-L105 and A549) cells (P < .001). The highest expression of CD62E was observed on hCMEC/D3 cells activated with TNF-α, with lower levels on metastatic NSCLC cells followed by primary NSCLC cells. Metastatic NSCLC cells adhered most strongly to hCMEC/D3 compared with primary NSCLC cells. CD15 immunoblocking decreased cancer cell adhesion to brain endothelium under static and shear stress conditions (P < .0001), confirming a correlation between CD15 and cerebral metastasis. Both CD15 and CD62E expression were detected in lung metastatic brain biopsies.
Conclusion
This study enhances the understanding of cancer cell-brain endothelial adhesion and confirms that CD15 plays a crucial role in adhesion in concert with TNF-α activation of its binding partner, CD62E.
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Grill, J., 2015-10-16 08:28:36 AM
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Rouse, C., Gittleman, H., Ostrom, Q. T., Kruchko, C., Barnholtz-Sloan, J. S., 2015-10-16 08:28:36 AM
Background
Years of potential life lost (YPLL) complement incidence and survival rates by measuring how much a patient's life is likely to be shortened by his or her cancer. In this study, we examine the impact of death due to brain and other central nervous system (CNS) tumors compared to other common cancers in adults by investigating the YPLL of adults in the United States.
Methods
Mortality and life table data were obtained from the Centers for Disease Control and Prevention's National Center for Health Statistics Vital Statistics Data for 2010. The study population included individuals aged 20 years or older at death who died from one of the selected cancers. YPLL was calculated by taking an individual's age at death and finding the corresponding expected remaining years of life using life table data.
Results
The cancers with the greatest mean YPLL were other malignant CNS tumors (20.65), malignant brain tumors (19.93), and pancreatic cancer (15.13) for males and malignant brain tumors (20.31), breast cancer (18.78), and other malignant CNS tumors (18.36) for females. For both sexes, non-Hispanic whites had the lowest YPLL, followed by non-Hispanic blacks, and Hispanics.
Conclusion
Malignant brain and other CNS tumors have the greatest mean YPLL, thereby reflecting their short survival time post diagnosis. These findings will hopefully motivate more research into mitigating the impact of these debilitating tumors.
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Wick, W., Platten, M., Wick, A., Hertenstein, A., Radbruch, A., Bendszus, M., Winkler, F., 2015-10-16 08:28:36 AM
Molecular targets for the pathological vasculature are the vascular endothelial growth factor (VEGF)/VEGF receptor axis, integrins, angiopoietins, and platelet-derived growth factor receptor (PDGFR), as well as several intracellular or downstream effectors like protein kinase C beta and mammalian target of rapamycin (mTOR). Besides hypoxic damage or tumor cell starvation, preclinical models imply vessel independent tumor regression and suggest differential effects of anti-angiogenic treatments on tumorous and nontumorous precursor cells or the immune system. Despite compelling preclinical data and positive data in other cancers, the outcomes of clinical trials with anti-angiogenic agents in gliomas by and large have been disappointing and include VEGF blockage with bevacizumab, integrin inhibition with cilengitide, VEGF receptor inhibition with sunitinib or cediranib, PDGFR inhibition with imatinib or dasatinib, protein kinase C inhibition with enzastaurin, and mTOR inhibition with sirolimus, everolimus, or temsirolimus. Importantly, there is a lack of real understanding for this negative data. Anti-angiogenic therapies have stimulated the development of standardized imaging assessment and the integration of functional MRI sequences into daily practice. Here, we delineate directions in the identification of molecularly or image-based defined subgroups, anti-angiogenic cotreatment for immunotherapy, and the potential of ongoing trials or modified targets to change the game.
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Veldhuijzen van Zanten, S. E. M., van Meerwijk, C. L. L. I., Jansen, M. H. A., Twisk, J. W. R., Anderson, A.-K., Coombes, L., Breen, M., Hargrave, O. J., Hemsley, J., Craig, F., Cruz, O., Kaspers, G. J. L., van Vuurden, D. G., Hargrave, D. R., on behalf of the SIOPE DIPG Network, 2015-10-16 08:28:36 AM
Background
More than 90% of patients with diffuse intrinsic pontine glioma (DIPG) will die within 2 years of diagnosis. Patients deteriorate rapidly during the disease course, which severely impairs their quality of life. To date, no specific research on this clinically important subject has been conducted. This study aimed to compile an inventory of symptoms experienced, interventions applied, and current service provision in end-of-life care for DIPG.
Methods
We performed a retrospective cohort study of children with DIPG, aged 0–18 years, who received treatment under the care of 2 London hospitals. Symptoms, interventions, and services applied during the 12 weeks before death were analyzed. In addition, we conducted a global questionnaire-study among health care professionals.
Results
In more than 78% of DIPG patients, problems concerning mobility, swallowing, communication, consciousness, and breathing arose during end-stage disease. Supportive drugs were widely prescribed. The use of medical aids was only documented in <15% of patients. Palliative and end-of-life care was mostly based on the health care professional's experience; only 21% of the questionnaire respondents reported to have a disease-specific palliative care guideline available.
Conclusions
This research assessed the current state of palliative and end-of-life care for children with DIPG. Our results show the variability and complexity of symptoms at end-stage disease and the current lack of disease-specific guidelines for this vulnerable group of patients. This first descriptive paper is intended to act as a solid basis for developing an international clinical trial and subsequent guideline to support high-quality palliative and end-of-life care.
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Butowski, N., Colman, H., De Groot, J. F., Omuro, A. M., Nayak, L., Wen, P. Y., Cloughesy, T. F., Marimuthu, A., Haidar, S., Perry, A., Huse, J., Phillips, J., West, B. L., Nolop, K. B., Hsu, H. H., Ligon, K. L., Molinaro, A. M., Prados, M., 2015-10-16 08:28:36 AM
Background
The colony stimulating factor 1 receptor (CSF1R) ligands, CSF1 and interleukin-34, and the KIT ligand, stem cell factor, are expressed in glioblastoma (GB). Microglia, macrophages, blood vessels, and tumor cells also express CSF1R, and depletion of the microglia reduces tumor burden and invasive capacity. PLX3397 is an oral, small molecule that selectively inhibits CSF1R and KIT, penetrates the blood–brain barrier in model systems, and represents a novel approach for clinical development.
Methods
We conducted a phase II study in patients with recurrent GB. The primary endpoint was 6-month progression-free survival (PFS6). Secondary endpoints included overall survival response rate, safety, and plasma/tumor tissue pharmacokinetics. Exploratory endpoints included pharmacodynamic measures of drug effect in blood and tumor tissue.
Results
A total of 37 patients were enrolled, with 13 treated prior to a planned surgical resection (Cohort 1) and 24 treated without surgery (Cohort 2). PLX3397 was given at an oral dose of 1000 mg daily and was well tolerated. The primary efficacy endpoint of PFS6 was only 8.6%, with no objective responses. Pharmacokinetic endpoints revealed a median maximal concentration (Cmax) of 8090 ng/mL, with a time to attain Cmax of 2 hour in plasma. Tumor tissue obtained after 7 days of drug exposure revealed a median drug level of 5500 ng/g. Pharmacodynamic changes included an increase in colony stimulating factor 1 and reduced CD14dim/CD16+ monocytes in plasma compared with pretreatment baseline values.
Conclusion
PLX3397 was well tolerated and readily crossed the blood–tumor barrier but showed no efficacy. Additional studies are ongoing, testing combination strategies and potential biomarkers to identify patients with greater likelihood of response.
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van der Vos, K. E., Abels, E. R., Zhang, X., Lai, C., Carrizosa, E., Oakley, D., Prabhakar, S., Mardini, O., Crommentuijn, M. H. W., Skog, J., Krichevsky, A. M., Stemmer-Rachamimov, A., Mempel, T. R., El Khoury, J., Hickman, S. E., Breakefield, X. O., 2015-10-16 08:28:36 AM
Background
To understand the ability of gliomas to manipulate their microenvironment, we visualized the transfer of vesicles and the effects of tumor-released extracellular RNA on the phenotype of microglia in culture and in vivo.
Methods
Extracellular vesicles (EVs) released from primary human glioblastoma (GBM) cells were isolated and microRNAs (miRNAs) were analyzed. Primary mouse microglia were exposed to GBM-EVs, and their uptake and effect on proliferation and levels of specific miRNAs, mRNAs, and proteins were analyzed. For in vivo analysis, mouse glioma cells were implanted in the brains of mice, and EV release and uptake by microglia and monocytes/macrophages were monitored by intravital 2-photon microscopy, immunohistochemistry, and fluorescence activated cell sorting analysis, as well as RNA and protein levels.
Results
Microglia avidly took up GBM-EVs, leading to increased proliferation and shifting of their cytokine profile toward immune suppression. High levels of miR-451/miR-21 in GBM-EVs were transferred to microglia with a decrease in the miR-451/miR-21 target c-Myc mRNA. In in vivo analysis, we directly visualized release of EVs from glioma cells and their uptake by microglia and monocytes/macrophages in brain. Dissociated microglia and monocytes/macrophages from tumor-bearing brains revealed increased levels of miR-21 and reduced levels of c-Myc mRNA.
Conclusions
Intravital microscopy confirms the release of EVs from gliomas and their uptake into microglia and monocytes/macrophages within the brain. Our studies also support functional effects of GBM-released EVs following uptake into microglia, associated in part with increased miRNA levels, decreased target mRNAs, and encoded proteins, presumably as a means for the tumor to manipulate its environs.
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Jones, K. A., Gilder, A. S., Lam, M. S., Du, N., Banki, M. A., Merati, A., Pizzo, D. P., VandenBerg, S. R., Gonias, S. L., 2015-10-16 08:28:36 AM
Background
In glioblastoma (GBM), the gene for epidermal growth factor receptor (EGFR) is frequently amplified. EGFR mutations also are common, including a truncation mutation that yields a constitutively active variant called EGFR variant (v)III. EGFRvIII-positive GBM progresses rapidly; however, the reason for this is not clear because the activity of EGFRvIII is attenuated compared with EGF-ligated wild-type EGFR. We hypothesized that EGFRvIII-expressing GBM cells selectively express other oncogenic receptors that support tumor progression.
Methods
Mining of The Cancer Genome Atlas prompted us to test whether GBM cells in culture, which express EGFRvIII, selectively express vascular endothelial growth factor receptor (VEGFR)2. We also studied human GBM propagated as xenografts. We then applied multiple approaches to test the effects of VEGFR2 on GBM cell growth, apoptosis, and cellular senescence.
Results
In human GBM, EGFR overexpression and EGFRvIII positivity were associated with increased VEGFR2 expression. In GBM cells in culture, EGFRvIII-initiated cell signaling increased expression of VEGFR2, which prevented cellular senescence and promoted cell cycle progression. The VEGFR-selective tyrosine kinase inhibitor cediranib decreased tumor DNA synthesis, increased staining for senescence-associated β-galactosidase, reduced retinoblastoma phosphorylation, and increased p27Kip1, all markers of cellular senescence. Similar results were obtained when VEGFR2 was silenced.
Conclusions
VEGFR2 expression by GBM cells supports cell cycle progression and prevents cellular senescence. Coexpression of VEGFR2 by GBM cells in which EGFR signaling is activated may contribute to the aggressive nature of these cells.
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Walbert, T., Pace, A., 2015-10-16 08:28:36 AM
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Berendsen, S., Varkila, M., Kroonen, J., Seute, T., Snijders, T. J., Kauw, F., Spliet, W. G. M., Willems, M., Poulet, C., Broekman, M. L., Bours, V., Robe, P. A., 2015-10-16 08:28:36 AM
Background
Epileptogenic glioblastomas are thought to convey a favorable prognosis, either due to early diagnosis or potential antitumor effects of antiepileptic drugs. We investigated the relationship between survival and epilepsy at presentation, early diagnosis, and antiepileptic drug therapy in glioblastoma patients.
Methods
Multivariable Cox regression was applied to survival data of 647 consecutive patients diagnosed with de novo glioblastoma between 2005 and 2013 in order to investigate the association between epilepsy and survival in glioblastoma patients. In addition, we quantified the association between survival and valproic acid (VPA) treatment.
Results
Epilepsy correlated positively with survival (HR: 0.75 (95% CI: 0.61–0.92), P < .01). This effect is independent of age, sex, performance status, type of surgery, adjuvant therapy, tumor location, and tumor volume, suggesting that this positive correlation cannot be attributed solely to early diagnosis. For patients who presented with epilepsy, the use of the antiepileptic drug VPA did not associate with survival when compared with patients who did not receive VPA treatment.
Conclusion
Epilepsy is an independent prognostic factor for longer survival in glioblastoma patients. This prognostic effect is not solely explained by early diagnosis, and survival is not associated with VPA treatment.
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Izquierdo, C., Velasco, R., Vidal, N., Sanchez, J. J., Argyriou, A. A., Besora, S., Graus, F., Bruna, J., 2015-10-16 08:28:36 AM
Background
Primary central nervous system lymphomas may present as diffuse, nonenhancing infiltrative lesions. This rare variant is termed lymphomatosis cerebri (LC). We did a systematic review and analysis of the literature, adding our own cases, to better characterize LC in order to improve early diagnosis and treatment.
Methods
PubMed, ISI Web of Knowledge, and hospital databases were reviewed. Information was extracted regarding demographic, clinical, histological, cerebrospinal fluid (CSF), neuroimaging, and treatment variables. The impact of single parameters on overall survival (OS) was determined by applying univariate and multivariate analyses.
Results
Forty-two patients were included (median age: 58 y; range: 28–80 y). At consultation, 52% of patients had a poor KPS. The most common presenting symptom was cognitive decline (59.5%). Imaging studies showed supratentorial and infratentorial infiltration in 55% of patients and bilateral hemispheric involvement in 95%. CSF pleocytosis was present in 51.5% of the patients. Median time to diagnosis was 4.5 (range: 1–30) months, and the diagnosis was not established until autopsy for 33% of patients. The median OS was 2.95 (range: 0.33–56) months; however, those patients who received methotrexate had a median OS of 13.8 (range: 0.7–56) months. Analysis identified KPS ≥ 70 (HR: 0.32; 95% CI: 0.114–0.894; P = .03) and treatment with methotrexate (HR: 0.19; 95% CI: 0.041–0.886; P = .034) as independent favorable prognostic factors, whereas T-cell lymphoma was independently related with a worse outcome (HR: 6.62; 95% CI: 1.317–33.316; P = .022).
Conclusions
LC is a misdiagnosed entity associated with considerable diagnostic delay. MRI evidence of bilateral hemispheric involvement and CSF pleocytosis should be alerts for this diagnosis. Treatment with methotrexate-based chemotherapy must be considered, especially for patients with good KPS.
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Cockle, J. V., Rajani, K., Zaidi, S., Kottke, T., Thompson, J., Diaz, R. M., Shim, K., Peterson, T., Parney, I. F., Short, S., Selby, P., Ilett, E., Melcher, A., Vile, R., 2015-10-16 08:28:36 AM
Background
Systemic delivery of a complementary cDNA library expressed from the vesicular stomatitis virus (VSV) treats tumors by vaccinating against a wide range of tumor associated antigens (TAAs). For subcutaneous B16 melanomas, therapy was achieved using a specific combination of self-TAAs (neuroblastoma-Ras, cytochrome c, and tyrosinase-related protein 1) expressed from VSV. However, for intracranial B16 tumors, a different combination was therapeutic (consisting of VSV-expressed hypoxia-inducible factor [HIF]–2α, Sox-10, c-Myc, and tyrosinase-related protein 1). Therefore, we tested the hypothesis that tumors of different histological types growing in the brain share a common immunogenic signature which can be exploited for immunotherapy.
Methods
Syngeneic tumors, including GL261 gliomas, in the brains of immune competent mice were analyzed for their antigenic profiles or were treated with systemic viroimmunotherapy.
Results
Several different histological types of tumors growing intracranially, as well as freshly resected human brain tumor explants, expressed a HIF-2αHi phenotype imposed by brain-derived CD11b+ cells. This location-specific antigen expression was exploited therapeutically against intracranial GL261 gliomas using systemically delivered VSV expressing HIF-2α, Sox-10, and c-Myc. Viroimmunotherapy was enhanced by immune checkpoint inhibitors, associated with the de-repression of antitumor T-helper cell type 1 (Th1) interferon- and Th17 T cell responses.
Conclusions
Since different tumor types growing in the same location in the brain share a location-specific phenotype, we suggest that antigen-specific immunotherapies should be based upon expression of both histological type–specific tumor antigens and location-specific antigens. Our findings support clinical application of VSV-TAA therapy with checkpoint inhibition for aggressive brain tumors and highlight the importance of the intracranial microenvironment in sculpting a location-specific profile of tumor antigen expression.
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Hou, L., Jiang, J., Liu, B., Han, W., Wu, Y., Zou, X., Nasca, P. C., Xue, F., Chen, Y., Zhang, B., Pang, H., Wang, Y., Wang, Z., Li, J., 2015-10-16 08:28:36 AM
Background
Smoking increases the risk of numerous cancers; however, an association of smoking with adult gliomas has not been found in a population.
Methods
This case-control study included 4556 glioma cases (ICD-9 code 191.0–191.9) aged ≥30 years and 9112 controls from a national survey of smoking and mortality in China in 1989–1991. Controls from 325 255 surviving spouses of all-cause deaths were randomly assigned to cases in each of 103 areas according to sex and age groups at a ratio of 2:1. Smoking information was ascertained retrospectively by interviewing surviving spouses.
Results
After adjustment for confounders, smoking increased the risk of glioma deaths by 11% (odds ratio [OR] = 1.11; 95% confidence interval [CI]: 1.03–1.21). Compared with non-smokers; the increased risk was 9% (OR = 1.09; 95% CI: 0.99–1.20) in men and 16% (OR = 1.16; 95% CI: 1.00–1.36) in women. The risk increased with age and doses. For individuals aged ≥50 years, smoking was associated with higher risk of glioma death by 25% (OR = 1.25; 95% CI: 1.15–1.38); this increased risk for smokers who smoked ≥20 cigarettes daily for ≥30 years was 53% (OR = 1.53; 95% CI: 1.34–1.74). There were similar findings in both men and women and with either pathology-based or non–pathology-based comparisons.
Conclusions
This study indicates that smoking is associated with glioma deaths in the Chinese population. Long-term heavy smoking could be a factor for risk stratification in individuals attending brain tumor clinics.
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Wang, K., Wang, Y., Fan, X., Wang, J., Li, G., Ma, J., Ma, J., Jiang, T., Dai, J., 2015-10-16 08:28:36 AM
Background
Radiological characteristics may reflect the biological features of brain tumors and may be associated with genetic alterations that occur in tumorigenesis. This study aimed to investigate the relationship between radiological features and IDH1 status as well as their predictive value for survival of glioblastoma patients.
Methods
The clinical information and MR images of 280 patients with histologically confirmed glioblastoma were retrospectively reviewed. The radiological characteristics of tumors were examined on MR images, and the IDH1status was determined using DNA sequencing for all cases. The Kaplan-Meier method and Cox regression model were used to identify prognostic factors for progression-free and overall survival.
Results
The IDH1 mutation was associated with longer progression-free survival (P = .022; hazard ratio, 0.602) and overall survival (P = .018; hazard ratio, 0.554). In patients with the IDH1 mutation, tumor contrast enhancement and peritumoral edema indicated worse progression-free survival (P = .015 and P = .024, respectively) and worse overall survival (P = .024 and P = .032, respectively). For tumors with contrast enhancement, multifocal contrast enhancement of the tumor lesion was associated with poor progression-free survival (P = .002) and poor overall survival (P = .010) in patients with wild-type IDH1 tumors.
Conclusions
Combining the radiological features and IDH1 status of a tumor allows more accurate prediction of survival outcomes in glioblastoma patients. The complementary roles of genetic changes and radiological features of tumors should be considered in future studies.
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Morana, G., Piccardo, A., Puntoni, M., Nozza, P., Cama, A., Raso, A., Mascelli, S., Massollo, M., Milanaccio, C., Garre, M. L., Rossi, A., 2015-10-16 08:28:36 AM
Background
1H-MR spectroscopy (MRS) and 18F-dihydroxyphenylalanine (DOPA) PET are noninvasive imaging techniques able to assess metabolic features of brain tumors. The aim of this study was to compare diagnostic and prognostic information gathered by 18F-DOPA PET and 1H-MRS in children with supratentorial infiltrative gliomas or nonneoplastic brain lesions suspected to be gliomas.
Methods
We retrospectively analyzed 27 pediatric patients with supratentorial infiltrative brain lesions on conventional MRI (21 gliomas and 6 nonneoplastic lesions) who underwent 18F-DOPA PET and 1H-MRS within 2 weeks of each other. 1H-MRS data (choline/N-acetylaspartate, choline-to-creatine ratios, and presence of lactate) and 18F-DOPA uptake parameters (lesion-to-normal tissue and lesion-to-striatum ratios) were compared and correlated with histology, WHO tumor grade, and patient outcome.
Results
1H-MRS and 18F-DOPA PET data were positively correlated. Sensitivity, specificity, and accuracy in distinguishing gliomas from nonneoplastic lesions were 95%, 83%, and 93% for 1H-MRS and 76%, 83%, and 78% for 18F-DOPA PET, respectively. No statistically significant differences were found between the 2 techniques (P > .05). Significant differences regarding 18F-DOPA uptake and 1H-MRS ratios were found between low-grade and high-grade gliomas (P≤.001 and P≤.04, respectively). On multivariate analysis, 18F-DOPA uptake independently correlated with progression-free survival (P≤.05) and overall survival (P = .04), whereas 1H-MRS did not show significant association with outcome.
Conclusions
1H-MRS and 18F-DOPA PET provide useful complementary information for evaluating the metabolism of pediatric brain lesions. 1H-MRS represents the method of first choice for differentiating brain gliomas from nonneoplastic lesions.18F-DOPA uptake better discriminates low-grade from high-grade gliomas and is an independent predictor of outcome.
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2015-10-16 08:28:36 AM
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Habets, E. J. J., Dirven, L., Wiggenraad, R. G., Verbeek-de Kanter, A., Lycklama a Nijeholt, G. J., Zwinkels, H., Klein, M., Taphoorn, M. J. B., 2015-10-16 08:28:36 AM
Background
Stereotactic radiotherapy (SRT) is expected to have a less detrimental effect on neurocognitive functioning and health-related quality of life (HRQoL) than whole-brain radiotherapy. To evaluate the impact of brain metastases and SRT on neurocognitive functioning and HRQoL, we performed a prospective study.
Methods
Neurocognitive functioning and HRQoL of 97 patients with brain metastases were measured before SRT and 1, 3, and 6 months after SRT. Seven cognitive domains were assessed. HRQoL was assessed with the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and BN20 questionnaires. Neurocognitive functioning and HRQoL over time were analyzed with linear mixed models and stratified for baseline Karnofsky performance status (KPS), total metastatic volume, and systemic disease.
Results
Median overall survival of patients was 7.7 months. Before SRT, neurocognitive domain and HRQoL scores were lower in patients than in healthy controls. At group level, patients worsened in physical functioning and fatigue at 6 months, while other outcome parameters of HRQoL and cognition remained stable. KPS < 90 and tumor volume >12.6 cm3 were both associated with worse information processing speed and lower HRQoL scores over 6 months time. Intracranial tumor progression was associated with worsening of executive functioning and motor function.
Conclusions
Prior to SRT, neurocognitive functioning and HRQoL are moderately impaired in patients with brain metastases. Lower baseline KPS and larger tumor volume are associated with worse functioning. Over time, SRT does not have an additional detrimental effect on neurocognitive functioning and HRQoL, suggesting that SRT may be preferred over whole-brain radiotherapy.
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Hellwinkel, J. E., Redzic, J. S., Harland, T. A., Gunaydin, D., Anchordoquy, T. J., Graner, M. W., 2015-10-16 08:28:36 AM
Background
Glioma-related immunosuppression is well documented; however, the mechanisms of suppression are not fully understood. Here we explore a role for glioma extracellular vesicles (EVs) as a means of immune modulation.
Methods
Healthy donor peripheral blood mononuclear cells (PBMCs) were incubated with mitogenic stimuli and various concentrations of glioma-derived EVs. Intracellular signaling and cytokine output were determined by protein microarrays, and phenotypic changes were assessed by flow cytometry. Recall antigen testing, mixed lymphocyte reactions, and migration assays analyzed PBMC functional capacity.
Results
Protein microarray data revealed induction of an immunosuppressive phenotype and cytokine output at high tumor-vesicle concentrations but an activated phenotype at low concentrations. T cell activation antigen expression confirmed differential activation profiles. Functional analyses revealed decreased migratory capacity of PBMCs after incubation with EVs; however, recall antigen and mixed lymphocyte tests indicated that activation capacity is still retained in EV-treated cells.
Conclusion
The differential effects of high and low EV concentrations dictate modulatory effects on PBMCs. These data provide a role for EVs at high concentrations for inducing selective tolerance of an immune response in a tumor setting. This suggests that lymphocytes in patients' circulation are not irreparably impaired, as previously thought, but can be rescued to augment antitumor responses.
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Alvarado, A. G., Turaga, S. M., Sathyan, P., Mulkearns-Hubert, E. E., Otvos, B., Silver, D. J., Hale, J. S., Flavahan, W. A., Zinn, P. O., Sinyuk, M., Li, M., Guda, M. R., Velpula, K. K., Tsung, A. J., Nakano, I., Vogelbaum, M. A., Majumder, S., Rich, J. N., Lathia, J. D., 2015-10-16 08:28:36 AM
Background
Cancer stem cells (CSCs) provide an additional layer of complexity for tumor models and targets for therapeutic development. The balance between CSC self-renewal and differentiation is driven by niche components including adhesion, which is a hallmark of stemness. While studies have demonstrated that the reduction of adhesion molecules, such as integrins and junctional adhesion molecule-A (JAM-A), decreases CSC maintenance. The molecular circuitry underlying these interactions has yet to be resolved.
Methods
MicroRNA screening predicted that microRNA-145 (miR-145) would bind to JAM-A. JAM-A overexpression in CSCs was evaluated both in vitro (proliferation and self-renewal) and in vivo (intracranial tumor initiation). miR-145 introduction into CSCs was similarly assessed in vitro. Additionally, The Cancer Genome Atlas dataset was evaluated for expression levels of miR-145 and overall survival of the different molecular groups.
Results
Using patient-derived glioblastoma CSCs, we confirmed that JAM-A is suppressed by miR-145. CSCs expressed low levels of miR-145, and its introduction decreased self-renewal through reductions in AKT signaling and stem cell marker (SOX2, OCT4, and NANOG) expression; JAM-A overexpression rescued these effects. These findings were predictive of patient survival, with a JAM-A/miR-145 signature robustly predicting poor patient prognosis.
Conclusions
Our results link CSC-specific niche signaling to a microRNA regulatory network that is altered in glioblastoma and can be targeted to attenuate CSC self-renewal.
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Shiroishi, M. S., Boxerman, J. L., Pope, W. B., 2015-10-16 08:28:36 AM
Aside from bidimensional measurements from conventional contrast-enhanced MRI, there are no validated or FDA-qualified imaging biomarkers for high-grade gliomas. However, advanced functional MRI techniques, including perfusion- and diffusion-weighted MRI, have demonstrated much potential for determining prognosis, predicting therapeutic response, and assessing early treatment response. They may also prove useful for differentiating pseudoprogression from true progression after temozolomide chemoradiation and pseudoresponse from true response after anti-angiogenic therapy. This review will highlight recent developments using these techniques and emphasize the need for technical standardization and validation in prospective studies in order for these methods to become incorporated into standard-of-care imaging for brain tumor patients.
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Filbin, M. G., Segal, R. A., 2015-10-16 08:28:36 AM
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Kocakaya, S., Beier, C. P., Beier, D., 2015-10-16 08:28:36 AM
Background
Adult medulloblastoma is a potentially curable malignant entity with an incidence of 0.5–1 per million. Valid data on prognosis, treatment, and demographics are lacking, as most current knowledge stems from retrospective studies. Surgical resection followed by radiotherapy are accepted parts of treatment regimes; however, established prognostic factors and data clarifying the role of chemotherapy are missing.
Methods
We investigated 227 publications from 1969–2013, with 907 identifiable, individual patients being available for meta-analysis. Demographic data, risk stratification, and treatment of these patients were similar to previous cohorts.
Results
The median overall survival (mOS) was 65 months (95% CI: 54.6–75.3) , the 5-year overall survival was 50.9% with 16% of the patients dying more than 5 years after diagnosis. Incomplete resection, clinical and radiological signs for brainstem infiltration, and abstinence from radiotherapy were predictive of worse outcome. Metastatic disease at tumor recurrence was identified as a new prognostic factor, while neither metastasis at initial diagnosis nor desmoplastic/classic histology was correlated with survival. Patients receiving chemotherapy first-line survived significantly longer (mOS: 108 mo, 95% CI: 68.6–148.4) than patients treated with radiation alone (mOS: 57 mo, 95% CI: 39.6–74.4) or patients who received chemotherapy at tumor recurrence. This effect was not biased by tumor stage or decade of treatment. Importantly, (neo)adjuvant chemotherapy also significantly increased the chance for long-term survival (>5 y) compared with radiotherapy alone or chemotherapy at tumor recurrence.
Conclusions
This meta-analysis clarifies relevant prognostic factors and suggests that chemotherapy as part of first-line therapy improves overall survival and increases the proportion of patients with long-term survival.
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Oberoi, R. K., Parrish, K. E., Sio, T. T., Mittapalli, R. K., Elmquist, W. F., Sarkaria, J. N., 2015-10-16 08:28:36 AM
Glioblastoma (GBM) is a lethal and aggressive brain tumor that is resistant to conventional radiation and cytotoxic chemotherapies. Molecularly targeted agents hold great promise in treating these genetically heterogeneous tumors, yet have produced disappointing results. One reason for the clinical failure of these novel therapies can be the inability of the drugs to achieve effective concentrations in the invasive regions beyond the bulk tumor. In this review, we describe the influence of the blood–brain barrier on the distribution of anticancer drugs to both the tumor core and infiltrative regions of GBM. We further describe potential strategies to overcome these drug delivery limitations. Understanding the key factors that limit drug delivery into brain tumors will guide future development of approaches for enhanced delivery of effective drugs to GBM.
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Basu, D., Salgado, C. M., Bauer, B. S., Johnson, D., Rundell, V., Nikiforova, M., Khakoo, Y., Gunwaldt, L. J., Panigrahy, A., Reyes-Mugica, M., 2015-10-16 08:28:36 AM
Background
Neurocutaneous melanocytosis (NCM) is characterized by clonal nevomelanocytic proliferations in the CNS and skin. Given the scarcity of effective therapeutic targets, testing new drugs requires a reliable and reproducible in vitro cellular model of the disease.
Methods
We generated nevomelanocytic spheroids in vitro from lesions of the spinal cord, brain, and skin from 4 NCM patients. Nevomelanocytic cells were grown as monolayers or spheroids and their growth characteristics were evaluated. Cultured cell identity was confirmed by demonstration of the same NRAS mutation found in the original lesions and by immunophenotyping. Nevomelanocytic spheroids were treated with inhibitors of specific mediators of the NRAS signaling pathway (vemurafenib, MEK162, GDC0941, and GSK2126458). Drug sensitivity and cell viability were assessed.
Results
Cultured cells were growth-factor dependent, grew as spheroids on Geltrex matrix, and maintained their clonogenicity in vitro over passages. Skin-derived cells formed more colonies than CNS-derived cells. Inhibitors of specific mediators of the NRAS signaling pathway reduced viability of NRAS mutated cells. The highest effect was obtained with GSK2126458, showing a viability reduction below 50%.
Conclusions
NRAS mutated cells derived from clinical NCM samples are capable of continuous growth as spheroid colonies in vitro and retain their genetic identity. Drugs targeting the NRAS signaling pathway reduce in vitro viability of NCM cells. NCM lesional spheroids represent a new and reliable experimental model of NCM for use in drug testing and mechanistic studies.
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Furtner, J., Schopf, V., Seystahl, K., Le Rhun, E., Ruda, R., Roelcke, U., Koeppen, S., Berghoff, A. S., Marosi, C., Clement, P., Faedi, M., Watts, C., Wick, W., Soffietti, R., Weller, M., Preusser, M., 2015-10-16 08:28:36 AM
Background
The efficacy of systemic antineoplastic therapy on recurrent World Health Organization (WHO) grades II and III meningiomas is unclear.
Methods
We performed a retrospective multicenter analysis of serial cranial MRI in patients with recurrent WHO II and III meningiomas treated with antineoplastic systemic therapies. Growth rates for tumor volume and diameter, as well as change rates for edema size, were calculated for all lesions.
Results
We identified a total of 34 patients (23 atypical, 11 anaplastic meningiomas) with a total of 57 meningioma lesions who had been treated at 6 European institutions. Systemic therapies included bevacizumab, cytotoxic chemotherapy, somatostatin analogues, and tyrosine kinase inhibitors. Overall, tumor growth rates decreased during systemic therapy by 51% for tumor diameter and 14% for tumor volume growth rates compared with the period before initiation of systemic therapy. The most pronounced decrease in meningioma growth rates during systemic therapy was evident in patients treated with bevacizumab, with a reduction of 80% in diameter and 59% in volume growth. Furthermore, a decrease in size of peritumoral edema after initiation of systemic therapy was exclusively observed in patients treated with bevacizumab (–107%).
Conclusions
Our data indicate that systemic therapy may inhibit growth of recurrent WHO grades II and III meningiomas to some extent. In our small cohort, bevacizumab had the most pronounced inhibitory effect on tumor growth, as well as some anti-edematous activity. Prospective studies are needed to better define the role of medical therapies in this tumor type.
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Dubbink, H. J., Atmodimedjo, P. N., Kros, J. M., French, P. J., Sanson, M., Idbaih, A., Wesseling, P., Enting, R., Spliet, W., Tijssen, C., Dinjens, W. N. M., Gorlia, T., van den Bent, M. J., 2015-10-16 08:28:36 AM
Background
Histopathological diagnosis of diffuse gliomas is subject to interobserver variation and correlates modestly with major prognostic and predictive molecular abnormalities. We investigated a series of patients with locally diagnosed anaplastic oligodendroglial tumors included in the EORTC phase III trial 26951 on procarbazine/lomustine/vincristine (PCV) chemotherapy to explore the diagnostic, prognostic, and predictive value of targeted next-generation sequencing (NGS) in diffuse glioma and to assess the prognostic impact ofFUBP1 and CIC mutations.
Methods
Mostly formalin-fixed paraffin-embedded samples were tested with targeted NGS for mutations in ATRX, TP53, IDH1, IDH2, CIC, FUBP1, PI3KC, TERT, EGFR, H3F3A, BRAF, PTEN, and NOTCH and for copy number alterations of chromosomes 1p, 19q, 10q, and 7. TERT mutations were also assessed, with PCR.
Results
Material was available from 139 cases, in 6 of which results were uninformative. One hundred twenty-six tumors could be classified: 20 as type II (IDH mutation [mut], "astrocytoma"), 49 as type I (1p/19q codeletion, "oligodendroglioma"), 55 as type III (7+/10q– or TERTmut and 1p/19q intact, "glioblastoma"), and 2 as childhood glioblastoma (H3F3Amut), leaving 7 unclassified (total 91% classified). Molecular classification was of clear prognostic significance and correlated better with outcome than did classical histopathology. In 1p/19q codeleted tumors, outcome was not affected by CIC and FUBP1 mutations. MGMT promoter methylation remained the most predictive factor for survival benefit of PCV chemotherapy.
Conclusion
Targeted NGS allows a clinically relevant classification of diffuse glioma into groups with very different outcomes. The diagnosis of diffuse glioma should be primarily based on a molecular classification, with the histopathological grade added to it. Future discussion should primarily aim at establishing the minimum requirements for molecular classification of diffuse glioma.
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Everson, R. G., Antonios, J. P., Lisiero, D. N., Soto, H., Scharnweber, R., Garrett, M. C., Yong, W. H., Li, N., Li, G., Kruse, C. A., Liau, L. M., Prins, R. M., 2015-10-16 08:28:36 AM
Background
Immunotherapy is an ideal treatment modality to specifically target the diffusely infiltrative tumor cells of malignant gliomas while sparing the normal brain parenchyma. However, progress in the development of these therapies for glioblastoma has been slow due to the lack of immunogenic antigen targets that are expressed uniformly and selectively by gliomas.
Methods
We utilized human glioblastoma cell cultures to induce expression of New York–esophageal squamous cell carcinoma (NY-ESO-1) following in vitro treatment with the demethylating agent decitabine. We then investigated the phenotype of lymphocytes specific for NY-ESO-1 using flow cytometry analysis and cytotoxicity against cells treated with decitabine using the xCelligence real-time cytotoxicity assay. Finally, we examined the in vivo application of this immune therapy using an intracranially implanted xenograft model for in situ T cell trafficking, survival, and tissue studies.
Results
Our studies showed that treatment of intracranial glioma–bearing mice with decitabine reliably and consistently induced the expression of an immunogenic tumor-rejection antigen, NY-ESO-1, specifically in glioma cells and not in normal brain tissue. The upregulation of NY-ESO-1 by intracranial gliomas was associated with the migration of adoptively transferred NY-ESO-1–specific lymphocytes along white matter tracts to these tumors in the brain. Similarly, NY-ESO-1–specific adoptive T cell therapy demonstrated antitumor activity after decitabine treatment and conferred a highly significant survival benefit to mice bearing established intracranial human glioma xenografts. Transfer of NY-ESO-1–specific T cells systemically was superior to intracranial administration and resulted in significantly extended and long-term survival of animals.
Conclusion
These results reveal an innovative, clinically feasible strategy for the treatment of glioblastoma.
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Aizer, A. A., Abedalthagafi, M., Linda Bi, W., Horvath, M. C., Arvold, N. D., Al-Mefty, O., Lee, E. Q., Nayak, L., Rinne, M. L., Norden, A. D., Reardon, D. A., Wen, P. Y., Ligon, K. L., Ligon, A. H., Beroukhim, R., Dunn, I. F., Santagata, S., Alexander, B. M., 2015-10-16 08:28:36 AM
Background
The appropriate use of adjuvant therapy in patients with gross totally resected atypical meningioma requires an accurate assessment of recurrence risk. We sought to determine whether cytogenetic/genetic characterization may facilitate better estimation of the probability of recurrence.
Methods
We first analyzed our clinical database, including high-resolution DNA copy number data, to identify 11 common copy number aberrations in a pilot cohort of meningiomas of all grades. We summed these aberrations to devise a cytogenetic abnormality score (CAS) and determined the CAS from archived tissue of a separate cohort of 32 patients with gross totally resected atypical meningioma managed with surgery alone. Propensity score adjusted Cox regression was used to determine whether the CAS was predictive of recurrence.
Results
An association between higher CAS and higher grade was noted in our pilot cohort with heterogeneity among atypical tumors. Among the 32 patients who underwent gross total resection of an atypical meningioma, the CAS was not significantly associated with age, gender, performance status, or tumor size/location but was associated with the risk of recurrence on univariable analysis (hazard ratio per aberration = 1.52; 95% CI = 1.08–2.14; P = .02). After adjustment, the impact of the dichotomized number of copy aberrations remained significantly associated with recurrence risk (hazard ratio = 4.47; 95% CI = 1.01–19.87; P = .05).
Conclusions
The number of copy number aberrations is strongly associated with recurrence risk in patients with atypical meningioma following gross total resection and may inform the appropriate use of adjuvant radiation therapy in these patients or be useful for stratification in clinical trials.
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Nduom, E. K., Wei, J., Yaghi, N. K., Huang, N., Kong, L.-Y., Gabrusiewicz, K., Ling, X., Zhou, S., Ivan, C., Chen, J. Q., Burks, J. K., Fuller, G. N., Calin, G. A., Conrad, C. A., Creasy, C., Ritthipichai, K., Radvanyi, L., Heimberger, A. B., 2015-10-16 08:28:36 AM
Background
Therapeutic targeting of the immune checkpoints cytotoxic T-lymphocyte-associated molecule-4 (CTLA-4) and PD-1/PD-L1 has demonstrated tumor regression in clinical trials, and phase 2 trials are ongoing in glioblastoma (GBM). Previous reports have suggested that responses are more frequent in patients with tumors that express PD-L1; however, this has been disputed. At issue is the validation of PD-L1 biomarker assays and prognostic impact.
Methods
Using immunohistochemical analysis, we measured the incidence of PD-L1 expression in 94 patients with GBM. We categorized our results according to the total number of PD-L1-expressing cells within the GBMs and then validated this finding in ex vivo GBM flow cytometry with further analysis of the T cell populations. We then evaluated the association between PD-L1 expression and median survival time using the protein expression datasets and mRNA from The Cancer Genome Atlas.
Results
The median percentage of PD-L1-expressing cells in GBM by cell surface staining is 2.77% (range: 0%–86.6%; n= 92), which is similar to the percentage found by ex vivo flow cytometry. The majority of GBM patients (61%) had tumors with at least 1% or more PD-L1-positive cells, and 38% had at least 5% or greater PD-L1 expression. PD-L1 is commonly expressed on the GBM-infiltrating T cells. Expression of both PD-L1 and PD-1 are negative prognosticators for GBM outcome.
Conclusions
The incidence of PD-L1 expression in GBM patients is frequent but is confined to a minority subpopulation, similar to other malignancies that have been profiled for PD-L1 expression. Higher expression of PD-L1 is correlated with worse outcome.
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Ruda, R., Bosa, C., Magistrello, M., Franchino, F., Pellerino, A., Fiano, V., Trevisan, M., Cassoni, P., Soffietti, R., 2015-10-16 08:28:36 AM
Background
Few data are available on temozolomide (TMZ) in ependymomas.
We investigated the response, survival, and correlation with MGMT promoter methylation in a cohort of patients with adult intracranial ependymoma receiving TMZ as salvage therapy after failure of surgery and radiotherapy.
Patients and Methods
We retrieved clinical information from the institutional database and follow-up visits, and response to TMZ on MRI was evaluated according to the MacDonald criteria.
Results
Eighteen patients (median age, 42 y), with either WHO grade III (10) or grade II (8) ependymoma were evaluable. Tumor location at diagnosis was supratentorial in 11 patients and infratentorial in 7. Progression before TMZ was local in 11 patients, local and spinal in 6 patients, and spinal only in one patient. A median of 8 cycles of TMZ (1–24) was administered. Response to TMZ consisted of complete response (CR) in one (5%) patient, partial response (PR) in 3 (17%) patients, stable disease (SD) in 7 (39%) patients, and progressive disease (PD) in 7 (39%) patients. Maximum response occurred after 3, 10, 14, and 15 cycles, respectively, with neurological improvement in 2 patients. All 4 responding patients were chemotherapy naïve. Both anaplastic (2) and grade II (2) tumors responded. Median progression-free survival and overall survival were 9.69 months (95% CI, 3.22–30.98) and 30.55 months (95% CI, 12.85–52.17), respectively. MGMT methylation was available in 11 patients and was not correlated with response or outcome.
Conclusion
TMZ has a role in recurrent chemo-naïve adult patients with intracranial ependymoma, regardless of tumor grade and MGMT methylation. We suggest that, after failure of surgery and radiotherapy, TMZ should be considered as a possible first-line treatment for recurrent ependymoma.
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Weber, D. C., Badiyan, S., Malyapa, R., Albertini, F., Bolsi, A., Lomax, A. J., Schneider, R., 2015-10-16 08:28:36 AM
Background
Skull-base chondrosarcoma (ChSa) is a rare disease, and the prognostication of this disease entity is ill defined.
Methods
We assessed the long-term local control (LC) results, overall survival (OS), and prognostic factors of skull-base ChSa patients treated with pencil beam scanning proton therapy (PBS PT). Seventy-seven (male, 35; 46%) patients with histologically confirmed ChSa were treated at the Paul Scherrer Institute. Median age was 38.9 years (range, 10.2–70.0y). Median delivered dose was 70.0 GyRBE (range, 64.0–76.0 GyRBE). LC, OS, and toxicity-free survival (TFS) rates were calculated using the Kaplan Meier method.
Results
After a mean follow-up of 69.2 months (range, 4.6–190.8 mo), 6 local (7.8%) failures were observed, 2 of which were late failures. Five (6.5%) patients died. The actuarial 8-year LC and OS were 89.7% and 93.5%, respectively. Tumor volume > 25 cm3 (P = .02), brainstem/optic apparatus compression at the time of PT (P = .04) and age >30 years (P = .08) were associated with lower rates of LC. High-grade (≥3) radiation-induced toxicity was observed in 6 (7.8%) patients. The 8-year high-grade TFS was 90.8%. A higher rate of high-grade toxicity was observed for older patients (P = .073), those with larger tumor volume (P = .069), and those treated with 5 weekly fractions (P = .069).
Conclusions
This is the largest PT series reporting the outcome of patients with low-grade ChSa of the skull base treated with PBS only. Our data indicate that protons are both safe and effective. Tumor volume, brainstem/optic apparatus compression, and age were prognosticators of local failures.
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Xia, S., Lal, B., Tung, B., Wang, S., Goodwin, C. R., Laterra, J., 2015-10-16 08:28:36 AM
Background
Glioblastoma (GBM) is the most frequent and aggressive primary brain tumor in adults. Recent research on cancer stroma indicates that the brain microenvironment plays a substantial role in tumor malignancy and treatment responses to current antitumor therapy. In this work, we have investigated the effect of alterations in brain tumor extracellular matrix tenascin-C (TNC) on brain tumor growth patterns including proliferation and invasion.
Methods
Since intracranial xenografts from patient-derived GBM neurospheres form highly invasive tumors that recapitulate the invasive features demonstrated in human patients diagnosed with GBM, we studied TNC gain-of-function and loss-of function in these GBM neurospheres in vitro and in vivo.
Results
TNC loss-of-function promoted GBM neurosphere cell adhesion and actin cytoskeleton organization. Yet, TNC loss-of-function or exogenous TNC had no effect on GBM neurosphere cell growth in vitro. In animal models, decreased TNC in the tumor microenvironment was accompanied by decreased tumor invasion and increased tumor proliferation, suggesting that TNC regulates the "go-or-grow" phenotypic switch of glioma in vivo. We demonstrated that decreased TNC in the tumor microenvironment modulated behaviors of stromal cells including endothelial cells and microglia, resulting in enlarged tumor blood vessels and activated microglia in tumors. We further demonstrated that tumor cells with decreased TNC expression are sensitive to anti-proliferative treatment in vitro.
Conclusion
Our findings suggest that detailed understanding of how TNC in the tumor microenvironment influences tumor behavior and the interactions between tumor cells and surrounding nontumor cells will benefit novel combinatory antitumor strategies to treat malignant brain tumors.
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Li, K.-L., Djoukhadar, I., Zhu, X., Zhao, S., Lloyd, S., McCabe, M., McBain, C., Evans, D. G., Jackson, A., 2015-10-16 08:28:36 AM
Background
Antiangiogenic therapy of vestibular schwannoma (VS) in type 2 neurofibromatosis can produce tumor shrinkage with response rates of 40%–60%. This study examines the predictive value of parameter-derived MRI in this setting.
Methods
Twelve patients with 20 VSs were recruited. Each had at least one rapidly growing tumor. Patients were treated with bevacizumab, 5 mg/kg every 2 weeks. Patients with stable or reduced VS volume were maintained at 2.5–5 mg every 4 weeks after 6 months. Those who failed treatment had their bevacizumab discontinued. Dynamic contrast-enhanced (DCE) MRI performed prior to treatment using a high temporal resolution technique, and data were analyzed to allow measurement of contrast transfer coefficient (Ktrans), vascular fraction (vp), extravascular-extracellular fraction (ve). Relaxation rate (R1N) was measured using a variable flip angle technique. Apparent diffusional coefficient (ADC) was calculated from diffusion-weighted imaging. The predictive power of microvascular parameters and ADC were examined using logistic regression modeling.
Results
Responding tumors were larger (P < .001), had lower R1N (P < .001), and higher Ktrans (P < .05) and ADC (P < .01). They showed increases in R1N (P < .01) and reduction of Ktrans (P < .01) and ADC (P < .01). Modeling to predict response demonstrated significant independent predictive power for R1N (B = – 0.327, P < .001), and Ktrans (B = 0.156, P < .05). Modeling to predict percentage change in tumor volume at 90 days identified baseline tumor volume (B = 5.503, P < .05), R1N (B = – 5.844, P < .05), and Ktrans (B = 5.622, P < .05) as independent significant predictors.
Conclusions
In patients with type 2 neurofibromatosis, biomarkers from DCE-MRI are predictive of VS volume response to inhibition of vascular endothelial growth factor inhibition.
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Armstrong, T. S., Vera-Bolanos, E., Acquaye, A. A., Gilbert, M. R., Ladha, H., Mendoza, T., 2015-10-16 08:28:36 AM
Background
A set of symptoms common across cancers has been proposed to enhance quality of care and clinical research in solid tumor patients. Using data from several clinical studies, this study evaluated these symptoms in primary brain tumor patients.
Methods
Symptom report data using the MD Anderson Symptom Instrument -Brain Tumor (MDASI-BT) from 621 patients enrolled in 8 clinical studies was used. The prevalence and severity of symptoms were reported as they relate to tumor grade, treatment stage and KPS.
Results
The sample was primarily white (82.5%) males (59%) with high-grade gliomas (75%). More than 50% of patients reported at least 10 concurrent symptoms, and 40% of patients reporting having at least 3 moderate-to-severe symptoms. Fatigue, drowsiness, difficulty remembering, disturbed sleep, and distress were the most severe symptoms reported by all tumor grades. Functional interference of symptoms with ability to work, perform activities, walk, and enjoy life was reported by more than 25% of patients.
Conclusions
These results support a core set of symptoms, common in other solid tumor patients, that may impact clinical care and assessment of treatment benefit. Although only 5 of the Center for Medical Technology Policy list of proposed core symptoms met criteria for inclusion in this sample, 5 of the other proposed core symptoms were also reported in similar frequency as reported in the other cancer populations. This primary brain tumor population differed from other solid tumor patients in that other symptoms, which could be disease related, were more prevalent and thus should also be collected for these patients.
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Ng, T., Teo, S. M., Yeo, H. L., Shwe, M., Gan, Y. X., Cheung, Y. T., Foo, K. M., Cham, M. T., Lee, J. A., Tan, Y. P., Fan, G., Yong, W. S., Preetha, M., Loh, W.-J. K., Koo, S.-L., Jain, A., Lee, G. E., Wong, M., Dent, R., Yap, Y. S., Ng, R., Khor, C. C., Ho, H. K., Chan, A., 2015-10-16 08:28:36 AM
Background
Brain-derived neurotrophic factor (BDNF), a neurotrophin that regulates neuronal function and development, is implicated in several neurodegenerative conditions. Preliminary data suggest that a reduction of BDNF concentrations may lead to postchemotherapy cognitive impairment. We hypothesized that a single nucleotide polymorphism (rs6265) of the BDNF gene may predispose patients to cognitive impairment. This study aimed to evaluate the effect of BDNF gene polymorphism on chemotherapy-associated cognitive impairment.
Methods
Overall, 145 patients receiving chemotherapy for early-stage breast cancer (mean age: 50.8 ± 8.8 y; 82.1% Chinese) were recruited. Patients' cognitive functions were assessed longitudinally using the validated Functional Assessment of Cancer Therapy–Cognitive Function (v.3) and an objective computerized tool, Headminder. Genotyping was performed using Sanger sequencing. Logistic regression was used to evaluate the association between BDNF Val66Met polymorphism and cognition after adjusting for ethnicity and clinically important covariates.
Results
Of the 145 patients, 54 (37%) reported cognitive impairment postchemotherapy. The Met/Met genotype was associated with statistically significant lower odds of developing cognitive impairment (odds ratio [OR] = 0.26; 95% CI: 0.08–0.92; P = .036). The Met carriers were less likely to experience impairment in the domains of verbal fluency (OR = 0.34; 95% CI: 0.12–0.90; P = .031) and multitasking ability (OR = 0.37; 95% CI: 0.15–0.91; P = .030) compared with the Val/Val homozygote. No associations were observed between Headminder and the BDNF Val66Met polymorphism.
Conclusions
This is the first study to provide evidence that carriers of the BDNF Met allele are protected against chemotherapy-associated cognitive impairment. Further studies are required to validate the findings.
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MacKeigan, J. P., Krueger, D. A., 2015-10-16 08:28:36 AM
Tuberous sclerosis complex (TSC) is a genetic autosomal dominant disorder characterized by benign tumor-like lesions, called hamartomas, in multiple organ systems, including the brain, skin, heart, kidneys, and lung. These hamartomas cause a diverse set of clinical problems based on their location and often result in epilepsy, learning difficulties, and behavioral problems. TSC is caused by mutations within the TSC1 or TSC2 genes that inactivate the genes' tumor-suppressive function and drive hamartomatous cell growth. In normal cells, TSC1 and TSC2integrate growth signals and nutrient inputs to downregulate signaling to mammalian target of rapamycin (mTOR), an evolutionarily conserved serine-threonine kinase that controls cell growth and cell survival. The molecular connection between TSC and mTOR led to the clinical use of allosteric mTOR inhibitors (sirolimus and everolimus) for the treatment of TSC. Everolimus is approved for subependymal giant cell astrocytomas and renal angiomyolipomas in patients with TSC. Sirolimus, though not approved for TSC, has undergone considerable investigation to treat various aspects of the disease. Everolimus and sirolimus selectively inhibit mTOR signaling with similar molecular mechanisms, but with distinct clinical profiles. This review differentiates mTOR inhibitors in TSC while describing the molecular mechanisms, pathogenic mutations, and clinical trial outcomes for managing TSC.
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Silver, D. J., Sinyuk, M., Vogelbaum, M. A., Ahluwalia, M. S., Lathia, J. D., 2015-10-16 08:28:36 AM
During brain neoplasia, malignant cells subjugate the immune system to provide an environment that favors tumor growth. These mechanisms capitalize on tumor-promoting functions of various immune cell types and typically result in suppression of tumor immune rejection. Immunotherapy efforts are underway to disrupt these mechanisms and turn the immune system against developing tumors. While many of these therapies are already in early-stage clinical trials, understanding how these therapies impact various tumor cell populations, including self-renewing cancer stem cells, may help to predict their efficacy and clarify their mechanisms of action. Moreover, interrogating the biology of glioma cell, cancer stem cell, and immune cell interactions may provide additional therapeutic targets to leverage against disease progression. In this review, we begin by highlighting a series of investigations into immune cell-mediated tumor promotion that do not parse the tumor into stem and non-stem components. We then take a closer look at the immune-suppressive mechanisms derived specifically from cancer stem cell interactions with the immune system and end with an update on immunotherapy and cancer stem cell-directed clinical trials in glioblastoma.
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Diamond, E. L., Russell, D., Kryza-Lacombe, M., Bowles, K. H., Applebaum, A. J., Dennis, J., DeAngelis, L. M., Prigerson, H. G., 2015-10-16 08:28:36 AM
Background
Primary malignant brain tumors (PMBTs) are devastating malignancies with poor prognosis. Optimizing psychosocial and supportive care is critical, especially in the later stages of disease.
Methods
This retrospective cohort study compared early versus late hospice enrollment of PMBT patients admitted to the home hospice program of a large urban, not-for-profit home health care agency between 2009 and 2013.
Results
Of 160 patients with PMBT followed to death in hospice care, 32 (22.5%) were enrolled within 7 days of death. When compared with patients referred to hospice more than 7 days before death, a greater proportion of those with late referral were bedbound at admission (97.2% vs 61.3%; OR=21.85; 95% CI, 3.42–919.20; P < .001), aphasic (61.1% vs 20.2%; OR = 6.13; 95% CI, 2.59–15.02; P < .001), unresponsive (38.9% vs 4%; OR = 14.76,;95% CI, 4.47–57.98; P < .001), or dyspneic (27.8% vs 9.7%; OR = 21.85; 95% CI, 3.42–10.12; P = .011). In multivariable analysis, male patients who were receiving Medicaid or charitable care and were without a health care proxy were more likely to enroll in hospice within 1 week of death.
Conclusions
Late hospice referral in PMBT is common. PMBT patients enrolled late in hospice are severely neurologically debilitated at the time hospice is initiated and therefore may not derive optimal benefit from multidisciplinary hospice care. Men, patients with lower socioeconomic status, and those without a health care proxy may be at risk for late hospice care and may benefit from proactive discussion about end-of-life care in PMBT, but prospective studies are needed.
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Zhu, Y., Zhao, K., Prinz, A., Keyvani, K., Lambertz, N., Kreitschmann-Andermahr, I., Lei, T., Sure, U., 2015-10-16 08:28:36 AM
Background
Neo-angiogenesis is a hallmark of glioblastoma (GBM) and is sustained by autocrine and paracrine interactions between neoplastic and nonneoplastic cells. Programmed cell death 10 (PDCD10) is ubiquitously expressed in nearly all tissues and plays crucial roles in regulating angiogenesis and apoptosis. We recently discovered the absence of PDCD10 expression in the tumor vessels of GBM patients. This raised the hypothesis that loss of endothelial PDCD10 affected GBM cell phenotyping and tumor progression.
Methods
Endothelial PDCD10 was silenced by siRNA and lentiviral shRNA. The tumor cell phenotype was studied in direct and indirect co-culture of endothelial cells (ECs) with U87 or LN229. Angiogenic protein array was performed in the media of PDCD10-silenced ECs. Tumor angiogenesis and tumor growth were investigated in a human GBM xenograft mouse model.
Results
Endothelial silence of PDCD10 significantly stimulated tumor cell proliferation, migration, adhesion, and invasion and inhibited apoptosis in co-cultures. Stable knockdown of endothelial PDCD10 increased microvessel density and the formation of a functional vascular network, leading to a 4-fold larger tumor mass in mice. Intriguingly, endothelial deletion of PDCD10 increased (≥2-fold) the release of 20 of 55 tested proangiogenic factors including VEGF, which in turn activated Erk1/2 and Akt in GBM cells.
Conclusions
For the first time, we provide evidence that loss of endothelial PDCD10 activates GBM cells and promotes tumor growth, most likely via a paracrine mechanism. PDCD10 shows a tumor-suppressor-like function in the cross talk between ECs and tumor cells and is potentially implicated in GBM progression.
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Bartels, R. H. M. A., de Ruiter, G., Feuth, T., Arts, M. P., 2015-10-16 08:28:36 AM
Background
The treatment of spinal epidural metastasis is multidisciplinary and usually involves a team of medical oncologists, radiologists, radiotherapists, and spinal surgeons. Life expectancy is one of the factors considered when deciding whether surgery is warranted. Because expert estimates of life expectancy are generally not reliable, a prediction model is needed. Here, we temporally validated a model that was previously validated geographically.
Methods
The records of 110 consecutive patients who were referred with a spinal epidural metastasis were collected prospectively from 2009 to 2013 in order to validate the model, which was published in 2011. The actual and estimated life expectancies were represented graphically, and calibration and discrimination were determined. The calibration slope, Harrell's c-index, D, and RD2 were calculated. Hazard ratios in the derivation set of 2011 were compared with the validation set. Misspecification was determined using the joint test for β*.
Results
The calibration slope was 0.64 ± 0.15 (95% CI: 0.34–0.94), Harrell's c-index was 0.72, D was 1.08, and RD2 was 0.22, indicating slightly worse discrimination in the derivation set. The joint test for β* = 0 was statistically significant and indicated misspecification; however, this misspecification was attributed entirely to the surgical group.
Conclusions
We validated a prediction model for surgical decision making, showing that the model's overall performance is good. Based on these results, this model will help clinicians to decide whether to offer surgery to patients with spinal epidural metastasis.
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Bluml, S., Margol, A. S., Sposto, R., Kennedy, R. J., Robison, N. J., Vali, M., Hung, L. T., Muthugounder, S., Finlay, J. L., Erdreich-Epstein, A., Gilles, F. H., Judkins, A. R., Krieger, M. D., Dhall, G., Nelson, M. D., Asgharzadeh, S., 2015-10-16 08:28:36 AM
Background
Medulloblastomas in children can be categorized into 4 molecular subgroups with differing clinical characteristics, such that subgroup determination aids in prognostication and risk-adaptive treatment strategies. Magnetic resonance spectroscopy (MRS) is a widely available, noninvasive tool that is used to determine the metabolic characteristics of tumors and provide diagnostic information without the need for tumor tissue. In this study, we investigated the hypothesis that metabolite concentrations measured by MRS would differ between molecular subgroups of medulloblastoma and allow accurate subgroup determination.
Methods
MRS was used to measure metabolites in medulloblastomas across molecular subgroups (SHH = 12, Groups 3/4 = 17, WNT = 1). Levels of 14 metabolites were analyzed to determine those that were the most discriminant for medulloblastoma subgroups in order to construct a multivariable classifier for distinguishing between combined Group 3/4 and SHH tumors.
Results
Medulloblastomas across molecular subgroups revealed distinct spectral features. Group 3 and Group 4 tumors demonstrated metabolic profiles with readily detectable taurine, lower levels of lipids, and high levels of creatine. SHH tumors showed prominent choline and lipid with low levels of creatine and little or no evidence of taurine. A 5-metabolite subgroup classifier inclusive of creatine, myo-inositol, taurine, aspartate, and lipid 13a was developed that could discriminate between Group 3/4 and SHH medulloblastomas with excellent accuracy (cross-validated area under the curve [AUC] = 0.88).
Conclusions
The data show that medulloblastomas of Group 3/4 differ metabolically as measured using MRS when compared with SHH molecular subgroups. MRS is a useful and accurate tool to determine medulloblastoma molecular subgroups.
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Baraniskin, A., Zaslavska, E., Nopel-Dunnebacke, S., Ahle, G., Seidel, S., Schlegel, U., Schmiegel, W., Hahn, S., Schroers, R., 2015-10-16 08:28:36 AM
Background
Primary central nervous system lymphomas (PCNSLs) are highly aggressive tumors. Chemotherapy has improved prognosis significantly; however, early diagnosis is crucial for effective treatment. Presently, the diagnosis of PCNSL depends on histopathology of tumor biopsies.
We have previously demonstrated differential expression of microRNAs in cerebrospinal fluid (CSF) samples from patients with PCNSL. Based on promising findings about circulating U2 small nuclear RNA fragments (RNU2-1f) as novel blood-based biomarkers for pancreatic, colorectal, and lung cancer, we investigated RNU2-1f in the CSF of PCNSL patients.
Methods
CSF was collected from patients with PCNSL (n = 72) and control patients with various neurologic disorders (n = 47). Sequential CSF samples were collected from 9 PCNSL patients. RNU2-1f levels were measured by real-time polymerase chain reaction.
Results
Measurement of RNU2-1f levels in CSF enabled the differentiation of patients with PCNSL from controls with an area under the curve (AUC) of 0.909 with a sensitivity of 68.1% and a specificity of 91.4%. The diagnostic accuracy was further improved by combined determination of RNU2-1f and miR-21, resulting in AUC of 0.987 with a sensitivity of 91.7% and a specificity of 95.7%. In consecutive measurements of RNU2-1f, which were performed in 9 patients at different stages of the disease course, RNU2-1f CSF levels paralleled the course of the disease.
Conclusions
Our data suggest that the measurement of RNU2-1f detected in CSF can be used as a diagnostic marker and also as a possible marker for treatment monitoring. These promising results need to be evaluated within a larger patient cohort.
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Davis, B., Shen, Y., Poon, C. C., Luchman, H. A., Stechishin, O. D., Pontifex, C. S., Wu, W., Kelly, J. J., Blough, M. D., for the Terry Fox Research Institute Glioblastoma Consortium, 2015-10-16 08:28:36 AM
Background
Glioblastoma (GBM) is a fatal cancer that has eluded major therapeutic advances. Failure to make progress may reflect the absence of a human GBM model that could be used to test compounds for anti-GBM activity. In this respect, the development of brain tumor-initiating cell (BTIC) cultures is a step forward because BTICs appear to capture the molecular diversity of GBM better than traditional glioma cell lines. Here, we perform a comparative genomic and genetic analysis of BTICs and their parent tumors as preliminary evaluation of the BTIC model.
Methods
We assessed single nucleotide polymorphisms (SNPs), genome-wide copy number variations (CNVs), gene expression patterns, and molecular subtypes of 11 established BTIC lines and matched parent tumors.
Results
Although CNV differences were noted, BTICs retained the major genomic alterations characteristic of GBM. SNP patterns were similar between BTICs and tumors. Importantly, recurring SNP or CNV alterations specific to BTICs were not seen. Comparative gene expression analysis and molecular subtyping revealed differences between BTICs and GBMs. These differences formed the basis of a 63-gene expression signature that distinguished cells from tumors; differentially expressed genes primarily involved metabolic processes. We also derived a set of 73 similarly expressed genes; these genes were not associated with specific biological functions.
Conclusions
Although not identical, established BTIC lines preserve the core molecular alterations seen in their parent tumors, as well as the genomic hallmarks of GBM, without acquiring recurring BTIC-specific changes.
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Dunet, V., Pomoni, A., Hottinger, A., Nicod-Lalonde, M., Prior, J. O., 2015-10-16 08:28:36 AM
Background
For the past decade 18F-fluoro-ethyl-l-tyrosine (FET) and 18F-fluoro-deoxy-glucose (FDG) positron emission tomography (PET) have been used for the assessment of patients with brain tumor. However, direct comparison studies reported only limited numbers of patients. Our purpose was to compare the diagnostic performance of FET and FDG-PET.
Methods
We examined studies published between January 1995 and January 2015 in the PubMed database. To be included the study should: (i) use FET and FDG-PET for the assessment of patients with isolated brain lesion and (ii) use histology as the gold standard. Analysis was performed on a per patient basis. Study quality was assessed with STARD and QUADAS criteria.
Results
Five studies (119 patients) were included. For the diagnosis of brain tumor, FET-PET demonstrated a pooled sensitivity of 0.94 (95% CI: 0.79–0.98) and pooled specificity of 0.88 (95% CI: 0.37–0.99), with an area under the curve of 0.96 (95% CI: 0.94–0.97), a positive likelihood ratio (LR+) of 8.1 (95% CI: 0.8–80.6), and a negative likelihood ratio (LR–) of 0.07 (95% CI: 0.02–0.30), while FDG-PET demonstrated a sensitivity of 0.38 (95% CI: 0.27–0.50) and specificity of 0.86 (95% CI: 0.31–0.99), with an area under the curve of 0.40 (95% CI: 0.36–0.44), an LR+ of 2.7 (95% CI: 0.3–27.8), and an LR– of 0.72 (95% CI: 0.47–1.11). Target-to-background ratios of either FDG or FET, however, allow distinction between low- and high-grade gliomas (P > .11).
Conclusions
For brain tumor diagnosis, FET-PET performed much better than FDG and should be preferred when assessing a new isolated brain tumor. For glioma grading, however, both tracers showed similar performances.
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Togao, O., Hiwatashi, A., Yamashita, K., Kikuchi, K., Mizoguchi, M., Yoshimoto, K., Suzuki, S. O., Iwaki, T., Obara, M., Van Cauteren, M., Honda, H., 2015-10-16 08:28:36 AM
Background
Our aim was to assess the diagnostic performance of intravoxel incoherent motion (IVIM) MR imaging for differentiating high-grade gliomas (HGGs) from low-grade gliomas (LGGs).
Methods
Forty-five patients with diffuse glioma (age 50.9 ± 20.4 y; 26 males, 19 females) were assessed with IVIM imaging using 13 b-values (0–1000 s/mm2) at 3T. The perfusion fraction (f), true diffusion coefficient (D), and pseudo-diffusion coefficient (D*) were calculated by fitting the bi-exponential model. The apparent diffusion coefficient (ADC) was obtained with 2 b-values (0 and 1000 s/mm2). Relative cerebral blood volume was measured by the dynamic susceptibility contrast method. Two observers independently measured D, ADC, D*, and f, and these measurements were compared between the LGG group (n = 16) and the HGG group (n = 29).
Results
Both D (1.26 ± 0.37 mm2/s in LGG, 0.94 ± 0.19 mm2/s in HGG; P < .001) and ADC (1.28 ± 0.35 mm2/s in LGG, 1.03 ± 0.19 mm2/s in HGG; P < .01) were lower in the HGG group. D was lower than ADC in the LGG (P < .05) and HGG groups (P < .0001). D* was not different between the groups. The f-values were significantly larger in HGG (17.5 ± 6.3%) than in LGG (5.8 ± 3.8%; P < .0001) and correlated with relative cerebral blood volume (r = 0.85; P < .0001). Receiver operating characteristic analyses showed areas under curve of 0.95 with f, 0.78 withD, 0.73 with ADC, and 0.60 with D*.
Conclusion
IVIM imaging is useful in differentiating HGGs from LGGs.
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Ringel, F., Pape, H., Sabel, M., Krex, D., Bock, H. C., Misch, M., Weyerbrock, A., Westermaier, T., Senft, C., Schucht, P., Meyer, B., Simon, M., the SN1 study group, the SN1 study group, Pape, Meyer, Ringel, Simon, Sabel, Rapp, Krex, Bock, Rohde, Weyerbrock, Machein, Westermaier, Ernestus, Franz, Senft, Schucht, Beck, Misch, Vajkoczy, Salehi, Nievas, Hollerhage, Schneider, Tapia-Perez, Hollig, Clusmann, Aumann, Kretschmer, Seiz-Rosenhagen, Thome, Buchalla, Gross, Stockhammer, Radovanovic, Schaller, Wolf, 2015-10-16 08:28:36 AM
Background
While standards for the treatment of newly diagnosed glioblastomas exist, therapeutic regimens for tumor recurrence remain mostly individualized. The role of a surgical resection of recurrent glioblastomas remains largely unclear at present. This study aimed to assess the effect of repeated resection of recurrent glioblastomas on patient survival.
Methods
In a multicenter retrospective-design study, patients with primary glioblastomas undergoing repeat resections for recurrent tumors were evaluated for factors affecting survival. Age, Karnofsky performance status (KPS), extent of resection (EOR), tumor location, and complications were assessed.
Results
Five hundred and three patients (initially diagnosed between 2006 and 2010) undergoing resections for recurrent glioblastoma at 20 institutions were included in the study. The patients' median overall survival after initial diagnosis was 25.0 months and 11.9 months after first re-resection. The following parameters were found to influence survival significantly after first re-resection: preoperative and postoperative KPS, EOR of first re-resection, and chemotherapy after first re-resection. The rate of permanent new deficits after first re-resection was 8%.
Conclusion
The present study supports the view that surgical resections of recurrent glioblastomas may help to prolong patient survival at an acceptable complication rate.
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Bull, K. S., Liossi, C., Peacock, J. L., Yuen, H. M., Kennedy, C. R., On Behalf of the Children's Cancer and Leukaemia Group (CCLG), 2015-10-16 08:28:36 AM
Background
We aimed to identify a brief screening measure for detection of cognitive deficit in children treated for cerebellar tumors that would be useful in clinical practice.
Methods
A sample of 72 children, aged 8–14 years, and within 3 years post diagnosis for standard-risk medulloblastoma (n = 37) or low-grade cerebellar astrocytoma (n = 35) and 38 children in a nontumor group were assessed using teacher-, parent-, and child-report of the Behavior Rating Inventory of Executive Function (BRIEF), Strengths and Difficulties Questionnaire (SDQ), and Pediatric Quality of Life Inventory (PedsQL). The accuracy of these scores as a screen for a full-scale Intelligence Quotient (FSIQ) < 80 on the Wechsler Intelligence Scale for Children (WISC-IV UK) was assessed using their receiver operating characteristic (ROC) curves.
Results
The questionnaires with the highest areas under the ROC curves were the child- and parent-report PedsQL, the teacher-report BRIEF, and the SDQ. At optimal cutoff scores, their sensitivities (95% CIs) to cases of FSIQ < 80 were 84 (60–96)%, 65 (41–84)%, 79 (54–93)%, and 84 (60–96)%, and their specificities (95% CIs) were 79 (68–86)%, 87 (77–93)%, 77 (66–86)%, and 71 (64–84)% respectively. All cases of FSIQ < 80 screened positive on either teacher-report SDQ or self-report PedsQL.
Conclusions
The PedsQL child- and parent-report and the teacher-report BRIEF and SDQ have moderately good accuracy for discriminating between children with and without a FSIQ < 80. The PedsQL could be used in a clinical setting, and the BRIEF and SDQ in an educational setting, to screen for cases with FSIQ < 80 in children treated for brain tumors.
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Lupo, J. M., Molinaro, A. M., Essock-Burns, E., Butowski, N., Chang, S. M., Cha, S., Nelson, S. J., 2015-10-16 08:28:36 AM
Background
Radiotherapy (RT) is an integral component in managing patients with glioma, but the damage it may cause to healthy brain tissue and quality of life is of concern. Susceptibility-weighted imaging (SWI) is highly sensitive to the detection of microbleeds that occur years after RT. This study's goals were to characterize the evolution of radiation-induced microbleeds in normal-appearing brain and determine whether the administration of an anti-angiogenic agent altered this process.
Methods
Serial high-resolution SWI was acquired on 17 patients with high-grade glioma between 8 months and 4.5 years posttreatment with RT and adjuvant chemotherapy. Nine of these patients were also treated with the anti-angiogenic agent enzastaurin. Microbleeds were identified as discrete foci of susceptibility not corresponding to vessels, tumor, or postoperative infarct, and counted in normal-appearing brain. Analysis of covariance was performed to compare slopes of regression of individual patients' microbleed counts over time, Wilcoxon rank-sum tests examined significant differences in rates of microbleed formation between groups, and linear and quadratic mixed-effects models were employed.
Results
The number of microbleeds increased with time for all patients, with initial onset occurring at 8–22 months. No microbleeds disappeared once formed. The average rate of microbleed formation significantly increased after 2 years post-RT (P < .001). Patients receiving anti-angiogenic therapy exhibited fewer microbleeds overall (P < .05) and a significant reduction in initial rate of microbleed appearance (P = .01).
Conclusions
We have demonstrated a dramatic increase in microbleed formation after 2 years post-RT that was decelerated by the concomitant administration of anti-angiogenic therapy, which may aid in determining brain regions susceptible to RT.
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Waitkus, M. S., Diplas, B. H., Yan, H., 2015-10-16 08:28:36 AM
Over the last decade, extraordinary progress has been made in elucidating the underlying genetic causes of gliomas. In 2008, our understanding of glioma genetics was revolutionized when mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) were identified in the vast majority of progressive gliomas and secondary glioblastomas (GBMs). IDH enzymes normally catalyze the decarboxylation of isocitrate to generate α-ketoglutarate (αKG), but recurrent mutations at Arg132 of IDH1 and Arg172 of IDH2 confer a neomorphic enzyme activity that catalyzes reduction of αKG into the putative oncometabolite D-2-hydroxyglutate (D2HG). D2HG inhibits αKG-dependent dioxygenases and is thought to create a cellular state permissive to malignant transformation by altering cellular epigenetics and blocking normal differentiation processes. Herein, we discuss the relevant literature on mechanistic studies of IDH1/2 mutations in gliomas, and we review the potential impact of IDH1/2mutations on molecular classification and glioma therapy.
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Macyszyn, L., Akbari, H., Pisapia, J. M., Da, X., Attiah, M., Pigrish, V., Bi, Y., Pal, S., Davuluri, R. V., Roccograndi, L., Dahmane, N., Martinez-Lage, M., Biros, G., Wolf, R. L., Bilello, M., O'Rourke, D. M., Davatzikos, C., 2015-10-16 08:28:36 AM
Background
MRI characteristics of brain gliomas have been used to predict clinical outcome and molecular tumor characteristics. However, previously reported imaging biomarkers have not been sufficiently accurate or reproducible to enter routine clinical practice and often rely on relatively simple MRI measures. The current study leverages advanced image analysis and machine learning algorithms to identify complex and reproducible imaging patterns predictive of overall survival and molecular subtype in glioblastoma (GB).
Methods
One hundred five patients with GB were first used to extract approximately 60 diverse features from preoperative multiparametric MRIs. These imaging features were used by a machine learning algorithm to derive imaging predictors of patient survival and molecular subtype. Cross-validation ensured generalizability of these predictors to new patients. Subsequently, the predictors were evaluated in a prospective cohort of 29 new patients.
Results
Survival curves yielded a hazard ratio of 10.64 for predicted long versus short survivors. The overall, 3-way (long/medium/short survival) accuracy in the prospective cohort approached 80%. Classification of patients into the 4 molecular subtypes of GB achieved 76% accuracy.
Conclusions
By employing machine learning techniques, we were able to demonstrate that imaging patterns are highly predictive of patient survival. Additionally, we found that GB subtypes have distinctive imaging phenotypes. These results reveal that when imaging markers related to infiltration, cell density, microvascularity, and blood–brain barrier compromise are integrated via advanced pattern analysis methods, they form very accurate predictive biomarkers. These predictive markers used solely preoperative images, hence they can significantly augment diagnosis and treatment of GB patients.
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Pallud, J., Audureau, E., Noel, G., Corns, R., Lechapt-Zalcman, E., Duntze, J., Pavlov, V., Guyotat, J., Hieu, P. D., Le Reste, P.-J., Faillot, T., Litre, C.-F., Desse, N., Petit, A., Emery, E., Voirin, J., Peltier, J., Caire, F., Vignes, J.-R., Barat, J.-L., Langlois, O., Dezamis, E., Parraga, E., Zanello, M., Nader, E., Lefranc, M., Bauchet, L., Devaux, B., Menei, P., Metellus, P., Club de Neuro-Oncologie of the Societe Francaise de Neurochirurgie, 2015-10-16 08:28:36 AM
Background
The standard of care for newly diagnosed glioblastoma is maximal safe surgical resection, followed by chemoradiation therapy. We assessed carmustine wafer implantation efficacy and safety when used in combination with standard care.
Methods
Included were adult patients with (n = 354, implantation group) and without (n = 433, standard group) carmustine wafer implantation during first surgical resection followed by chemoradiation standard protocol. Multivariate and case-matched analyses (controlled propensity-matched cohort, 262 pairs of patients) were conducted.
Results
The median progression-free survival was 12.0 months (95% CI: 10.7–12.6) in the implantation group and 10.0 months (9.0–10.0) in the standard group and the median overall survival was 20.4 months (19.0–22.7) and 18.0 months (17.0–19.0), respectively. Carmustine wafer implantation was independently associated with longer progression-free survival in patients with subtotal/total surgical resection in the whole series (adjusted hazard ratio [HR], 0.76 [95% CI: 0.63–0.92], P = .005) and after propensity matching (HR, 0.74 [95% CI: 0.60–0.92], P= .008), whereas no significant difference was found for overall survival (HR, 0.95 [0.80–1.13], P = .574; HR, 1.06 [0.87–1.29], P = .561, respectively). Surgical resection at progression whether alone or combined with carmustine wafer implantation was independently associated with longer overall survival in the whole series (HR, 0.58 [0.44–0.76], P < .0001; HR, 0.54 [0.41–0.70], P < .0001, respectively) and after propensity matching (HR, 0.56 [95% CI: 0.40–0.78], P < .0001; HR, 0.46 [95% CI: 0.33–0.64], P < .0001, respectively). The higher postoperative infection rate in the implantation group did not affect survival.
Conclusions
Carmustine wafer implantation during surgical resection followed by the standard chemoradiation protocol for newly diagnosed glioblastoma in adults resulted in a significant progression-free survival benefit.
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Friedman, G. K., Moore, B. P., Nan, L., Kelly, V. M., Etminan, T., Langford, C. P., Xu, H., Han, X., Markert, J. M., Beierle, E. A., Gillespie, G. Y., 2015-10-16 08:28:36 AM
Background
Childhood medulloblastoma is associated with significant morbidity and mortality that is compounded by neurotoxicity for the developing brain caused by current therapies, including surgery, craniospinal radiation, and chemotherapy. Innate therapeutic resistance of some aggressive pediatric medulloblastoma has been attributed to a subpopulation of cells, termed cancer-initiating cells or cancer stemlike cells (CSCs), marked by the surface protein CD133 or CD15. Brain tumors characteristically contain areas of pathophysiologic hypoxia, which has been shown to drive the CSC phenotype leading to heightened invasiveness, angiogenesis, and metastasis. Novel therapies that target medulloblastoma CSCs are needed to improve outcomes and decrease toxicity. We hypothesized that oncolytic engineered herpes simplex virus (oHSV) therapy could effectively infect and kill pediatric medulloblastoma cells, including CSCs marked by CD133 or CD15.
Methods
Using 4 human pediatric medulloblastoma xenografts, including 3 molecular subgroup 3 tumors, which portend worse patient outcomes, we determined the expression of CD133, CD15, and the primary HSV-1 entry molecule nectin-1 (CD111) by fluorescence activated cell sorting (FACS) analysis. Infectability and cytotoxicity of clinically relevant oHSVs (G207 and M002) were determined in vitro and in vivo by FACS, immunofluorescent staining, cytotoxicity assays, and murine survival studies.
Results
We demonstrate that hypoxia increased the CD133+ cell fraction, while having the opposite effect on CD15 expression. We established that all 4 xenografts, including the CSCs, expressed CD111 and were highly sensitive to killing by G207 or M002.
Conclusions
Pediatric medulloblastoma, including Group 3 tumors, may be an excellent target for oHSV virotherapy, and a clinical trial in medulloblastoma is warranted.
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Agnihotri, S., Zadeh, G., 2015-10-16 08:28:36 AM
A defining hallmark of glioblastoma is altered tumor metabolism. The metabolic shift towards aerobic glycolysis with reprogramming of mitochondrial oxidative phosphorylation, regardless of oxygen availability, is a phenomenon known as the Warburg effect. In addition to the Warburg effect, glioblastoma tumor cells also utilize the tricarboxylic acid cycle/oxidative phosphorylation in a different capacity than normal tissue. Altered metabolic enzymes and their metabolites are oncogenic and not simply a product of tumor proliferation. Here we highlight the advantages of why tumor cells, including glioblastoma cells, require metabolic reprogramming and how tumor metabolism can converge on tumor epigenetics and unanswered questions in the field.
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Ouyang, Q., Chen, G., Zhou, J., Li, L., Dong, Z., Yang, R., Xu, L., Cui, H., Xu, M., Yi, L., 2015-10-16 08:28:36 AM
Background
Neurotensin (NTS) and its primary receptor NTSR1 are implicated in cancer progression. Aberrant expression of NTS/NTSR1 contributes to the proliferation of glioblastoma cells; however, the mechanism is not fully understood.
Methods
Microarray and real-time PCR were performed to identify the NTS-regulated micro (mi)RNAs. The targets of the miRNAs were identified by luciferase assays and immunoblot analysis. The c-Myc binding sites in the miR-29b-1 and cyclin-dependent kinase (CDK)4 promoters were identified through chromatin immunoprecipitation assay. Cell proliferation was evaluated by Cell Counting Kit-8 assay and flow cytometry analysis. An orthotopic xenograft model demonstrated the role of NTS/NTSR1 and miRNAs in glioblastoma growth in vivo.
Results
Pharmacological inhibition or small interfering NTSR1 treatment blocked glioblastoma cell cycle progression in the G1 phase with a concomitantly decreased expression of CDK6, CDK4, and c-Myc. Knockdown of NTSR1 increased the expression of miR-29b-1 and miR-129-3p, which were responsible for the decreased CDK6 expression. NTS/NTSR1 signaling activated the transcription factor c-Myc in U87 cells, leading to increased CDK4 expression and repressed miR-29b-1 expression. Knockdown of NTSR1 decreased the glioblastoma growth in vivo and significantly prolonged the survival time of the tumor-bearing mice, an effect that can be largely reversed by antagomir.
Conclusions
Our study showed a novel regulatory mechanism of NTS/NTSR1, an upstream signaling of miRNAs and c-Myc, in glioblastoma progression. The inhibition of the NTSR1 function or the upregulation of miR-29b-1 and miR-129-3p expression impaired glioma cell proliferation. These results suggested that the NTS/NTSR1/c-Myc/miRNA axis may be a potential therapeutic target for glioblastoma therapy.
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Harshyne, L. A., Nasca, B. J., Kenyon, L. C., Andrews, D. W., Hooper, D. C., 2015-10-16 08:28:36 AM
Background
Glioblastoma (GBM) is an aggressive infiltrative brain tumor with a particularly poor prognosis that is characterized by microvascular proliferation, necrotic tissue, and significant infiltration of M2-like monocytes. Compromised barrier function in tumor vasculature might be expected to permit communication between the tumor microenvironment and peripheral blood.
Methods
To ascertain whether tumor-derived vesicles and/or factors might reach the bloodstream and what effects these molecules have on the peripheral compartment, we analyzed blood samples collected from primary GBM patients.
Results
Notably, a significant number of patient sera samples contained tumor exosome-reactive immunoglobulin (Ig)G2 and IgG4 antibody isotypes, which are consistent with Th2 immunity. M2-like monocytes expressing CD14+ and CD163+, another indicator of Th2 bias, are elevated in GBM patient blood and associated with high serum concentrations of colony–stimulating factor 2 and 3, as well as interleukin-2, -4, and -13, the latter 2 cytokines being hallmarks of Th2 immunity. GBM patient sera samples induce high levels of CD163 expression when added to normal monocytes, providing mechanistic evidence of a basis for Th2 bias. Fractionation of GBM patient sera into samples enriched for exosomes or soluble factors proved that both fractions are capable of inducing CD163 expression in normal monocytes.
Conclusions
The results of the current study indicate a Th2 bias in the periphery of GBM patients, likely as a result of products elaborated by the tumor. Consequentially, through immune modulation these brain tumors exert systemic effects beyond the confines of the CNS.
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Gong, Y., Ma, Y., Sinyuk, M., Loganathan, S., Thompson, R. C., Sarkaria, J. N., Chen, W., Lathia, J. D., Mobley, B. C., Clark, S. W., Wang, J., 2015-10-16 08:28:36 AM
Background
Metabolic complications such as obesity, hyperglycemia, and type 2 diabetes are associated with poor outcomes in patients with glioblastoma. To control peritumoral edema, use of chronic high-dose steroids in glioblastoma patients is common, which can result in de novo diabetic symptoms. These metabolic complications may affect tumors via profound mechanisms, including activation of insulin receptor (InsR) and the related insulin-like growth factor 1 receptor (IGF1R) in malignant cells.
Methods
In the present study, we assessed expression of InsR in glioblastoma surgical specimens and glioblastoma response to insulin at physiologically relevant concentrations. We further determined whether genetic or pharmacological targeting of InsR affected oncogenic functions of glioblastoma in vitro and in vivo.
Results
We showed that InsR was commonly expressed in glioblastoma surgical specimens and xenograft tumor lines, with mitogenic isoform-A predominating. Insulin at physiologically relevant concentrations promoted glioblastoma cell growth and survival, potentially via Akt activation. Depletion of InsR impaired cellular functions and repressed orthotopic tumor growth. The absence of InsR compromised downstream Akt activity, but yet stimulated IGF1R expression. Targeting both InsR and IGF1R with dual kinase inhibitors resulted in effective blockade of downstream signaling, loss of cell viability, and repression of xenograft tumor growth.
Conclusions
Taken together, our work suggests that glioblastoma is sensitive to the mitogenic functions of insulin, thus significant insulin exposure imposes risks to glioblastoma patients. Additionally, dual inhibition of InsR and IGF1R exhibits promise for treating glioblastoma.
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Ramaswamy, V., Remke, M., Adamski, J., Bartels, U., Tabori, U., Wang, X., Huang, A., Hawkins, C., Mabbott, D., Laperriere, N., Taylor, M. D., Bouffet, E., 2015-10-16 08:28:36 AM
Background
The advent of integrated genomics has fundamentally changed our understanding of medulloblastoma. Although survival differences exist among the 4 principal subgroups, this has yet to be elucidated in a North American cohort of irradiated patients.
Methods
Ninety-two consecutive patients between the ages of 3 and 17 treated with surgery, craniospinal irradiation, and chemotherapy were identified at the Hospital for Sick Children. Molecular subgrouping was performed using nanoString.
Results
Two treatment periods were identified: prior to 2006 as per the protocols of the Children's Oncology Group, and after 2006 per the St Jude Medulloblastoma 03 protocol. Five-year progression-free survival (PFS) over the entire cohort was 0.801 (95% CI: 0.692–0.875) with no significant difference between treatment protocols. Strikingly, we found that Group 4 patients had excellent 5-year PFS of 0.959 (95% CI: 0.744–0.994) for average risk and 0.887 (95% CI: 0.727–0.956) across all Group 4 patients. Group 3 patients had 5-year PFS of 0.733 (95% CI: 0.436–0.891). Sonic hedgehog patients did poorly across both treatment protocols, with 5-year PFS of 0.613 (95% CI: 0.333–0.804), likely owing to a high proportion of TP53 mutated patients in this age group.
Conclusions
In a cohort of irradiated patients over 3 years of age, PFS for Group 4 patients was significantly improved compared with initial reports. The impact of subgroup affiliation in these children needs to be assessed in large prospectively treated cooperative protocols to determine if more than just WNT patients can be safely selected for de-escalation of therapy.
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Patel, A. V., Johansson, G., Colbert, M. C., Dasgupta, B., Ratner, N., 2015-10-16 08:28:36 AM
Background
Malignant peripheral nerve sheath tumors (MPNSTs) are soft tissue sarcomas with minimal therapeutic opportunities. We observed that lipid droplets (LDs) accumulate in human MPNST cell lines and in primary human tumor samples. The goal of this study was to investigate the relevance of lipid metabolism to MPNST survival and as a possible therapeutic target.
Methods
Based on preliminary findings that MPNSTs accumulate LDs, we hypothesized that a deregulated lipid metabolism supports MPNST cell survival/proliferation rate. To test this, we examined respiration, role of fatty acid oxidation (FAO), and the enzyme fatty acid synthase involved in de novo fatty acid synthesis in MPNSTs using both genetic and pharmacological tools.
Results
We demonstrate that LDs accumulate in MPNST cell lines, primary human and mouse MPNST tumors, and neural crest cells. LDs from MPNST cells disappear on lipid deprivation, indicating that LDs can be oxidized as a source of energy. Inhibition of FAO decreased oxygen consumption and reduced MPNST survival, indicating that MPNST cells likely metabolize LDs through active FAO. FAO inhibition reduced oxygen consumption and survival even in the absence of exogenous lipids, indicating that lipids synthesized de novo can also be oxidized. Consequently, inhibition of de novo fatty acid synthesis, which is overexpressed in human MPNST cell lines, effectively reduced MPNST survival and delayed induction of tumor growth in vivo.
Conclusion
Our results show that MPNSTs depend on lipid metabolic pathways and suggest that disrupting lipid metabolism could be a potential new strategy for the development of MPNST therapeutics.
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Feichtinger, R. G., Weis, S., Mayr, J. A., Zimmermann, F. A., Bogner, B., Sperl, W., Kofler, B., 2015-10-16 08:28:36 AM
Background
Changes in the mode of aerobic energy production are observed in many solid tumors, though the kinds of changes differ among tumor types. We investigated mitochondrial energy metabolism in meningiomas and peripheral nerve sheath tumors, taking into consideration the histologic heterogeneity of these tumors.
Methods
Oxidative phosphorylation (OXPHOS) complexes and porin (a marker for mitochondrial mass) were analyzed by immunohistochemical staining of meningiomas (n = 76) and peripheral nerve sheath tumors (schwannomas: n = 10; neurofibromas: n = 4). The enzymatic activities of OXPHOS complexes and citrate synthase were determined by spectrophotometric measurement. Western blot analysis of OXPHOS complexes, porin, and mitochondrial transcription factor A was performed. Furthermore, mitochondrial DNA copy number was determined.
Results
The tumors differed with regard to mitochondrial energy metabolism. Low levels of a subset of OXPHOS complexes were frequently observed in World Health Organization grade I meningiomas (percent of cases with a reduction; complex I: 63%; complex II: 67%; complex IV: 56%) and schwannomas (complex III: 40%, complex IV: 100%), whereas in neurofibromas a general reduction of all complexes was observed. In contrast, expression of complexes III and V was similar to that in normal brain tissue in the majority of tumors. Mitochondrial mass was comparable or higher in all tumors compared with normal brain tissue, whereas mitochondrial DNA copy number was reduced.
Conclusions
The reduction of OXPHOS complexes in meningiomas and peripheral nerve sheath tumors has potential therapeutic implications, since respiratory chain–deficient tumor cells might be selectively starved by inhibitors of glycolysis or by ketogenic diet.
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Acquaye, A. A., Lin, L., Vera-Bolanos, E., Gilbert, M. R., Armstrong, T. S., 2015-10-16 08:28:36 AM
Background
The ambiguity of defining hope impacts the level of readiness faced by health care professionals treating patients with glioma, a disease with unpredictable outcomes. This study describes the report of hope and the relationship between hope and mood in adult brain tumor patients at various points in the illness trajectory.
Methods
This was a cross-sectional study with data collection including use of the Herth Hope Index (HHI), the Profile of Mood States-Short Form (POMS-SF), and clinical information. Descriptive statistics were used to report sample characteristics. Spearman's rho and Mann-Whitney tests were used to compare and differentiate scores.
Results
Eighty-two patients ranging in age from 22 to 78 years (median, 44.5 y) participated in the study. Patients were primarily male (57.3%), married (76.8%), and had a high-grade glioma (35.4%). Nearly half had recurrence, and more than 20% were on active treatment. The overall HHI total score for the sample was 41.32 (range: 13–48). Patients with recurrence had a lower HHI interconnectedness (median = 14.00) score and higher total mood disturbance (median = 14.00) compared with patients without recurrence (median = 15.00 and median = 0.00, respectively; P < .05). All negative mood states on the POMS-SF were negatively correlated with HHI subscales.
Conclusions
Overall, patients reporting more hope also reported less overall mood disturbance As expected, patients with tumor recurrence reported lower hope and higher mood disturbance than those who were newly diagnosed or without recurrence. Targeting interventions specifically tailored to an individual's needs for improvement in quality of life throughout the disease course may include measures to address hope in order to facilitate positive coping strategies.
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Seliger, C., Ricci, C., Meier, C. R., Bodmer, M., Jick, S. S., Bogdahn, U., Hau, P., Leitzmann, M. F., 2015-10-16 08:28:36 AM
Background
Prior epidemiologic studies suggest inverse relations between diabetes and glioma risk, but the underlying mechanisms, including use of antidiabetic drugs, are unknown.
Methods
We therefore performed a matched case-control analysis using the Clinical Practice Research Datalink (CPRD). We identified incident glioma cases diagnosed between 1995 and 2012 and matched each case with 10 controls on age, gender, calendar time, general practice, and years of active history in the CPRD. We performed conditional logistic regression to estimate odds ratios (ORs) with 95% CIs, adjusted for body mass index and smoking.
Results
We identified 2005 cases and 20 050 controls. Diabetes was associated with decreased risk of glioma (OR = 0.74; 95% CI = 0.60–0.93), particularly glioblastoma (OR = 0.69; 95% CI = 0.51–0.94). Glioblastoma risk reduction was markedly pronounced among diabetic men (OR = 0.60; 95% CI = 0.40–0.90), most apparently for those with diabetes of long-term duration (OR for >5 vs 0 y = 0.46; 95% CI = 0.26–0.82) or poor glycemic control (OR for HbA1c ≥8 vs <6.5% = 0.20; 95% CI = 0.06–0.70). In contrast, the effect of diabetes on glioblastoma risk was absent among women (OR = 0.85; 95% CI = 0.53–1.36). No significant associations with glioma were found for use of metformin (OR for ≥30 vs 0 prescriptions = 0.72; 95% CI = 0.38–1.39), sulfonylureas (OR = 0.71; 95% CI = 0.39–1.30), or insulin (OR = 0.79; 95% CI = 0.37–1.69).
Conclusions
Antidiabetic treatment appears to be unrelated to glioma, but long-term diabetes duration and increased HbA1c both show decreased glioma risk. Stronger findings in men than women suggest low androgen levels concurrent with diabetes as a biologic mechanism.
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Lee, J.-K., Chang, N., Yoon, Y., Yang, H., Cho, H., Kim, E., Shin, Y., Kang, W., Oh, Y. T., Mun, G. I., Joo, K. M., Nam, D.-H., Lee, J., 2015-10-16 08:28:36 AM
Background
Clinical benefits from standard therapies against glioblastoma (GBM) are limited in part due to intrinsic radio- and chemoresistance of GBM and inefficient targeting of GBM stem-like cells (GSCs). Novel therapeutic approaches that overcome treatment resistance and diminish stem-like properties of GBM are needed.
Methods
We determined the expression levels of ubiquitination-specific proteases (USPs) by transcriptome analysis and found that USP1 is highly expressed in GBM. Using the patient GBM-derived primary tumor cells, we inhibited USP1 by shRNA-mediated knockdown or its specific inhibitor pimozide and evaluated the effects on stem cell marker expression, proliferation, and clonogenic growth of tumor cells.
Results
USP1 was highly expressed in gliomas relative to normal brain tissues and more preferentially in GSC enrichment marker (CD133 or CD15) positive cells. USP1 positively regulated the protein stability of the ID1 and CHEK1, critical regulators of DNA damage response and stem cell maintenance. Targeting USP1 by RNA interference or treatment with a chemical USP1 inhibitor attenuated clonogenic growth and survival of GSCs and enhanced radiosensitivity of GBM cells. Finally, USP1 inhibition alone or in combination with radiation significantly prolonged the survival of tumor-bearing mice.
Conclusion
USP1-mediated protein stabilization promotes GSC maintenance and treatment resistance, thereby providing a rationale for USP1 inhibition as a potential therapeutic approach against GBM.
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Zhou, Y., Wu, S., Liang, C., Lin, Y., Zou, Y., Li, K., Lu, B., Shu, M., Huang, Y., Zhu, W., Kang, Z., Xu, D., Hu, J., Yan, G., 2015-10-16 08:28:36 AM
Background
Malignant glioma is the most lethal primary tumor of the central nervous system, with notable cell invasion causing significant recurrence. Suppression of glioma invasion is very important for improving clinical outcomes. Drugs that directly disrupt the cytoskeleton have been developed for this purpose; however, drug resistance and unsatisfactory selectivity have limited their clinical use. Previously, we reported that protein kinase A (PKA, also known as cyclic-AMP dependent protein kinase) activation induced the differentiation of glioma cells.
Methods
We used several small molecular inhibitors and RNA interference, combined with wound healing assays, Matrigel transwell assay, and microscopic observation, to determine whether activation of the PKA pathway could inhibit the invasion of human glioma cells.
Results
Activation of PKA decreased the invasion of glioma cells. The mechanism operated via transcriptional upregulation of microtubule-associated protein 2 (MAP2), which was activated by the PKA pathway and led to ossification of microtubule dynamics via polymerization of tubulin. This resulted in morphological changes and a reduction in glioma cell invasion. Furthermore, chromosome immunoprecipitation and quantitative real-time polymerase chain reaction showed that signal transducer and activator of transcription 3 (STAT3) is involved in the transcriptional upregulation of MAP2.
Conclusion
Our findings suggested that PKA may represent a potential target for anti-invasion glioma therapy and that the downstream modulators (eg, STAT3/MAP2) partially mediate the effects of PKA.
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Rapkins, R. W., Wang, F., Nguyen, H. N., Cloughesy, T. F., Lai, A., Ha, W., Nowak, A. K., Hitchins, M. P., McDonald, K. L., 2015-10-16 08:28:36 AM
Background
Promoter methylation of O6-methylguanine-DNA methyltransferase (MGMT) is an important predictive biomarker in glioblastoma. The T variant of the MGMT promoter-enhancer single nucleotide polymorphism (SNP; rs16906252) has been associated with the presence of MGMT promoter methylation in other cancers. We examined the association of the T allele of rs16906252 with glioblastoma development, tumor MGMT methylation, MGMT protein expression, and survival outcomes.
Methods
Two independent temozolomide-treated glioblastoma cohorts—one Australian (Australian Genomics and Clinical Outcomes of Glioma, n = 163) and the other American (University of California Los Angeles/Kaiser Permanente Los Angeles, n = 159)—were studied. Allelic bisulphite sequencing was used to determine if methylation was specific to the T allele. Additionally, we compared the incidence of the T allele between glioblastoma cases and matched controls to assess whether it was a risk factor for developing MGMT methylated glioblastoma.
Results
Carriage of the T allele of the rs16906252 SNP was associated with both MGMT methylation and low MGMT protein expression and predicted significantly longer survival in temozolomide-treated patients with both MGMTmethylated and nonmethylated glioblastoma. Methylation was linked to the T allele, inferring that the T variant plays a key role in the acquisition of MGMT methylation. Carriage of the T allele was associated with a significantly elevated risk of developing glioblastoma (adjusted odds ratio, 1.96; P = .013), increasing further when glioblastoma was classified by the presence of MGMT methylation (adjusted odds ratio, 2.86; P = .001).
Conclusions
The T allele of the rs16906252 SNP is a key determinant in the acquisition of MGMT methylation in glioblastoma. Temozolomide-treated patients with the rs16906252 T genotype have better survival, irrespective of tumor methylation status.
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Schatlo, B., Fandino, J., Smoll, N. R., Wetzel, O., Remonda, L., Marbacher, S., Perrig, W., Landolt, H., Fathi, A.-R., 2015-10-16 08:28:36 AM
Background
Previous studies have shown the individual benefits of 5-aminolevulinic acid (5-ALA) and intraoperative (i)MRI in enhancing survival for patients with high-grade glioma. In this retrospective study, we compare rates of progression-free and overall survival between patients who underwent surgical resection with the combination of 5-ALA and iMRI and a control group without iMRI.
Methods
In 200 consecutive patients with high-grade gliomas, we recorded age, sex, World Health Organization tumor grade, and pre- and postoperative Karnofsky performance status (good ≥80 and poor <80). A 0.15-Tesla magnet was used for iMRI; all patients operated on with iMRI received 5-ALA. Overall and progression-free survival rates were compared using multivariable regression analysis.
Results
Median overall survival was 13.8 months in the non-iMRI group and 17.9 months in the iMRI group (P = .043). However, on identifying confounding variables (ie, KPS and resection status) in this univariate analysis, we then adjusted for these confounders in multivariate analysis and eliminated this distinction in overall survival (hazard ratio: 1.23, P = .34, 95% CI: 0.81, 1.86). Although 5-ALA enhanced the achievement of gross total resection (odds ratio: 3.19, P = .01, 95% CI: 1.28, 7.93), it offered no effect on overall or progression-free survival when adjusted for resection status.
Conclusions
Gross total resection is the key surgical variable that influences progression and survival in patients with high-grade glioma and more likely when surgical adjuncts, such as iMRI in combination with 5-ALA, are used to enhance resection.
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Studebaker, A. W., Hutzen, B., Pierson, C. R., Shaffer, T. A., Raffel, C., Jackson, E. M., 2015-10-16 08:28:36 AM
Background
Atypical teratoid rhabdoid tumor (AT/RT) is a rare, highly malignant pediatric tumor of the central nervous system that is usually refractory to available treatments. The aggressive growth, propensity to disseminate along the neuroaxis, and young age at diagnosis contribute to the poor prognosis. Previous studies have demonstrated the efficacy of using oncolytic measles virus (MV) against localized and disseminated models of medulloblastoma. The purpose of this study was to evaluate the oncolytic potential of MV in experimental models of AT/RT.
Methods
Following confirmation of susceptibility to MV infection and killing of AT/RT cells in vitro, nude mice were injected with BT-12 and BT-16 AT/RT cells stereotactically into the caudate nucleus (primary tumor model) or lateral ventricle (disseminated tumor model). Recombinant MV was administered either intratumorally or intravenously. Survival was determined for treated and control animals. Necropsy was performed on animals showing signs of progressive disease.
Results
All cell lines exhibited significant killing when infected with MV, all formed syncytia with infection, and all generated infectious virus after infection. Orthotopic xenografts displayed cells with rhabdoid-like cellular morphology, were negative for INI1 expression, and showed dissemination within the intracranial and spinal subarachnoid spaces. Intratumoral injection of live MV significantly prolonged the survival of animals with intracranial and metastatic tumors.
Conclusion
These data demonstrate that AT/RT is susceptible to MV killing and suggest that the virus may have a role in treating this tumor in the clinical setting.
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2015-10-16 08:28:34 AM
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2015-10-16 08:28:34 AM
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2015-10-16 08:28:34 AM
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2015-10-16 08:28:34 AM
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Hegi, M. E., Stupp, R., 2015-10-16 08:28:34 AM
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Walker, P. R., Migliorini, D., 2015-10-16 08:28:34 AM
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Bhat, Pope, Huse, Hegi, Aldape, 2015-10-16 08:28:34 AM
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Galldiks, N., Langen, K.-J., Pope, W. B., 2015-10-16 08:28:34 AM
The most common type of primary brain tumor is malignant glioma. Despite intensive therapeutic efforts, the majority of these neoplasms remain incurable. Imaging techniques are important for initial tumor detection and comprise indispensable tools for monitoring treatment. Structural imaging using contrast-enhanced MRI is the method of choice for brain tumor surveillance, but its capacity to differentiate tumor from nonspecific tissue changes can be limited, particularly with posttreatment gliomas. Metabolic imaging using positron-emission-tomography (PET) can provide relevant additional information, which may allow for better assessment of tumor burden in ambiguous cases. Specific PET tracers have addressed numerous molecular targets in the last decades, but only a few have achieved relevance in routine clinical practice. At present, PET studies using radiolabeled amino acids appear to improve clinical decision-making as these tracers can offer better delineation of tumor extent as well as improved targeting of biopsies, surgical interventions, and radiation therapy. Amino acid PET imaging also appears useful for distinguishing glioma recurrence or progression from postradiation treatment effects, particularly radiation necrosis and pseudoprogression, and provides information on histological grading and patient prognosis. In the last decade, the tracers O-(2-[18F]fluoroethyl)-L-tyrosine (FET) and 3,4-dihydroxy-6-[18F]-fluoro-L-phenylalanine (FDOPA) have been increasingly used for these indications. This review article focuses on these tracers and summarizes their recent applications for patients with brain tumors. Current uses of tracers other than FET and FDOPA are also discussed, and the most frequent practical questions regarding PET brain tumor imaging are reviewed.
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Walsh, K. M., Wiencke, J. K., Lachance, D. H., Wiemels, J. L., Molinaro, A. M., Eckel-Passow, J. E., Jenkins, R. B., Wrensch, M. R., 2015-10-16 08:28:34 AM
A growing body of epidemiologic and tumor genomic research has identified an important role for telomere maintenance in glioma susceptibility, initiation, and prognosis. Telomere length has long been investigated in relation to cancer, but whether longer or shorter telomere length might be associated with glioma risk has remained elusive. Recent data address this question and are reviewed here. Common inherited variants near the telomerase-component genes TERC and TERT are associated both with longer telomere length and increased risk of glioma. Exome sequencing of glioma patients from families with multiple affected members has identified rare inherited mutations in POT1 (protection of telomeres protein 1) as high-penetrance glioma risk factors. These heritable POT1 mutations are also associated with increased telomere length in leukocytes. Tumor sequencing studies further indicate that acquired somatic mutations of TERT and ATRX are among the most frequent alterations found in adult gliomas. These mutations facilitate telomere lengthening, thus bypassing a critical mechanism of apoptosis. Although future research is needed, mounting evidence suggests that glioma is, at least in part, a disease of telomere dysregulation. Specifically, several inherited and acquired variants underlying gliomagenesis affect telomere pathways and are also associated with increased telomere length.
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Chonan, M., Saito, R., Shoji, T., Shibahara, I., Kanamori, M., Sonoda, Y., Watanabe, M., Kikuchi, T., Ishii, N., Tominaga, T., 2015-10-16 08:28:34 AM
Background
The prognosis of glioblastoma (GBM) remains poor; therefore, effective therapeutic strategies need to be developed. CD40 is a costimulatory molecule whose agonistic antibody has been shown to activate antitumor effects. Recently, CD40 has been extensively targeted for immunotherapeutic purposes.
Methods
Expressions of CD40/CD40L mRNAs were examined in 86 cases of World Health Organization grade IV GBM and 36 cases of grade III gliomas and correlated with outcomes. CD40 signaling was employed to augment the efficacy of immunotherapy against gliomas. The efficacy of FGK45, an agonistic antibody for CD40, was examined by adding it to a tumor lysate–based subcutaneous vaccination against a GL261 glioma model and an NSCL61 glioma-initiating cell–like cell tumor model.
Results
We demonstrated for the first time using quantitative PCR that grade III gliomas express higher levels of CD40/CD40L than does grade IV GBM. The higher expression of CD40/CD40L was associated with good prognoses in patients with GBM. Addition of FGK45 to the subcutaneous tumor cell lysate–based vaccination significantly prolonged survival in both tumor models. However, the efficacy was modest in NSCL61-model mice. Therefore, we established combination immunotherapeutic strategies using FGK45 and OX86, an agonistic antibody for OX40. Combination immunotherapy significantly prolonged survival with synergistic effects. Apoptosis increased and proliferation decreased in tumors treated with combination immunotherapy.
Conclusions
The high expression of CD40/CD40L can be used as a biomarker for better prognoses in patients with gliomas. Immunotherapy using FGK45 significantly prolonged survival and represents a potential therapeutic strategy for gliomas including glioma-initiating cells.
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Singh, M. M., Johnson, B., Venkatarayan, A., Flores, E. R., Zhang, J., Su, X., Barton, M., Lang, F., Chandra, J., 2015-10-16 08:28:34 AM
Background
Glioblastoma (GBM) is the most common and aggressive form of brain cancer. Our previous studies demonstrated that combined inhibition of HDAC and KDM1A increases apoptotic cell death in vitro. However, whether this combination also increases death of the glioma stem cell (GSC) population or has an effect in vivo is yet to be determined. Therefore, we evaluated the translational potential of combined HDAC and KDM1A inhibition on patient-derived GSCs and xenograft GBM mouse models. We also investigated the changes in transcriptional programing induced by the combination in an effort to understand the induced molecular mechanisms of GBM cell death.
Methods
Patient-derived GSCs were treated with the combination of vorinostat, a pan-HDAC inhibitor, and tranylcypromine, a KDM1A inhibitor, and viability was measured. To characterize transcriptional profiles associated with cell death, we used RNA-Seq and validated gene changes by RT-qPCR and protein expression via Western blot. Apoptosis was measured using DNA fragmentation assays. Orthotopic xenograft studies were conducted to evaluate the effects of the combination on tumorigenesis and to validate gene changes in vivo.
Results
The combination of vorinostat and tranylcypromine reduced GSC viability and displayed efficacy in the U87 xenograft model. Additionally, the combination led to changes in apoptosis-related genes, particularly TP53 and TP73 in vitro and in vivo.
Conclusions
These data support targeting HDACs and KDM1A in combination as a strategy for GBM and identifies TP53 and TP73 as being altered in response to treatment.
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Dong, F., Eibach, M., Bartsch, J. W., Dolga, A. M., Schlomann, U., Conrad, C., Schieber, S., Schilling, O., Biniossek, M. L., Culmsee, C., Strik, H., Koller, G., Carl, B., Nimsky, C., 2015-10-16 08:28:34 AM
Background
Despite multimodal treatment, glioblastoma (GBM) therapy with temozolomide (TMZ) remains inefficient due to chemoresistance. Matrix metalloproteinase (MMP) and a disintegrin and metalloprotease (ADAM), increased in GBM, could contribute to chemoresistance and TMZ-induced recurrence of glioblastoma.
Methods
TMZ inducibility of metalloproteases was determined in GBM cell lines, primary GBM cells, and tissues from GBM and recurrent GBM. TMZ sensitivity and invasiveness of GBM cells were assessed in the presence of the metalloprotease inhibitors batimastat (BB-94) and marimastat (BB-2516). Metalloprotease-dependent effects of TMZ on mitochondria and pAkt/phosphatidylinositol-3 kinase (PI3K) and phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) pathways were analyzed by fluorescence activated cell sorting, morphometry, and immunoblotting. Invasiveness of GBM cells was determined by Matrigel invasion assays. Potential metalloprotease substrates were identified by proteomics and tested for invasion using blocking antibodies.
Results
TMZ induces expression of MMP-1, -9, -14, and ADAM8 in GBM cells and in recurrent GBM tissues. BB-94, but not BB-2516 (ADAM8-sparing) increased TMZ sensitivity of TMZ-resistant and -nonresistant GBM cells with different O6-methylguanine-DNA methyltransferase states, suggesting that ADAM8 mediates chemoresistance, which was confirmed by ADAM8 knockdown, ADAM8 overexpression, or pharmacological inhibition of ADAM8. Levels of pAkt and pERK1/2 were increased in GBM cells and correlated with ADAM8 expression, cell survival, and invasiveness. Soluble hepatocyte growth factor (HGF) R/c-met and CD44 were identified as metalloprotease substrates in TMZ-treated GBM cells. Blocking of HGF R/c-met prevented TMZ-induced invasiveness.
Conclusions
ADAM8 causes TMZ resistance in GBM cells by enhancing pAkt/PI3K, pERK1/2, and cleavage of CD44 and HGF R/c-met. Specific ADAM8 inhibition can optimize TMZ chemotherapy of GBM in order to prevent formation of recurrent GBM in patients.
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Bergthold, G., Bandopadhayay, P., Hoshida, Y., Ramkissoon, S., Ramkissoon, L., Rich, B., Maire, C. L., Paolella, B. R., Schumacher, S. E., Tabak, B., Ferrer-Luna, R., Ozek, M., Sav, A., Santagata, S., Wen, P. Y., Goumnerova, L. C., Ligon, A. H., Stiles, C., Segal, R., Golub, T., Grill, J., Ligon, K. L., Chan, J. A., Kieran, M. W., Beroukhim, R., 2015-10-16 08:28:34 AM
Background
Pediatric low-grade gliomas (PLGGs), the most frequent pediatric brain tumor, comprise a heterogeneous group of diseases. Recent genomic analyses suggest that these tumors are mostly driven by mitogene-activated protein kinase (MAPK) pathway alterations. However, little is known about the molecular characteristics inherent to their clinical and histological heterogeneity.
Methods
We performed gene expression profiling on 151 paraffin-embedded PLGGs from different locations, ages, and histologies. Using unsupervised and supervised analyses, we compared molecular features with age, location, histology, and BRAF genomic status. We compared molecular differences with normal pediatric brain expression profiles to observe whether those patterns were mirrored in normal brain.
Results
Unsupervised clustering distinguished 3 molecular groups that correlated with location in the brain and histological subtype. "Not otherwise specified" (NOS) tumors did not constitute a unified class. Supratentorial pilocytic astrocytomas (PAs) were significantly enriched with genes involved in pathways related to inflammatory activity compared with infratentorial tumors. Differences based on tumor location were not mirrored in location-dependent differences in expression within normal brain tissue. We identified significant differences between supratentorial PAs and diffuse astrocytomas as well as between supratentorial PAs and dysembryoplastic neuroepithelial tumors but not between supratentorial PAs and gangliogliomas. Similar expression patterns were observed between childhood and adolescent PAs. We identified differences between BRAF-duplicated and V600E-mutated tumors but not between primary and recurrent PLGGs.
Conclusion
Expression profiling of PLGGs reveals significant differences associated with tumor location, histology, and BRAFgenomic status. Supratentorial PAs, in particular, are enriched in inflammatory pathways that appear to be tumor-related.
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Viaccoz, A., Ducray, F., Tholance, Y., Barcelos, G. K., Thomas-Maisonneuve, L., Ghesquieres, H., Meyronet, D., Quadrio, I., Cartalat-Carel, S., Louis-Tisserand, G., Jouanneau, E., Guyotat, J., Honnorat, J., Perret-Liaudet, A., 2015-10-16 08:28:34 AM
Background
The diagnosis of primary central nervous system lymphoma (PCNSL) can be challenging. PCNSL lesions are frequently located deep within the brain, and performing a cerebral biopsy is not always feasible. The aim of this study was to investigate the diagnostic value of CSF neopterin, a marker of neuroinflammation, in immunocompetent patients with suspected PCNSL.
Methods
We retrospectively reviewed the characteristics of 124 patients with brain tumor (n = 82) or an inflammatory CNS disorder (n = 42) in whom CSF neopterin levels were assessed. Twenty-eight patients had PCNSL, 54 patients had another type of brain tumor (glioma n = 36, metastasis n = 13, other n = 5), and 13 patients had a pseudotumoral inflammatory brain lesion.
Results
CSF neopterin levels were significantly higher in the patients with PCNSL than in those with other brain tumors (41.8 vs 5.1 nmol/L, P < .001), those with pseudotumoral inflammatory brain lesions (41.8 vs 4.3 nmol/L, P < .001), and those with nontumefactive inflammatory CNS disorders (41.8 vs 3.8 nmol/L, P < .001). In the 95 patients with space-occupying brain lesions, at a cutoff of 10 nmol/L, the sensitivity of this approach was 96% and the specificity was 93% for the diagnosis of PCNSL. The positive and negative predictive values were 84% and 98%, respectively.
Conclusion
Assessing CSF neopterin levels in patients with a suspected brain tumor might be helpful for the positive and differential diagnosis of PCNSL. A prospective study is warranted to confirm these results.
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Field, K. M., Simes, J., Nowak, A. K., Cher, L., Wheeler, H., Hovey, E. J., Brown, C. S. B., Barnes, E. H., Sawkins, K., Livingstone, A., Freilich, R., Phal, P. M., Fitt, G., CABARET/COGNO investigators, Rosenthal, M. A., CABARET/COGNO investigators, Field, Simes, Hovey, Nowak, Cher, Wheeler, Brown, Barnes, Sawkins, Livingstone, Rosenthal, Phal, Fitt, Goh, Tattersall, Kelly, Hayden, Sawkins, Brown, Barnes, Livingstone, Winter, Tomes, Pike, Simes, Freilich, Arzhintar, Field, Rosenthal, Garrett, Simes, Byrne, Dowling, Ranieri, Jennens, Osmond, Patterson, Phay, Abell, Plowman, Cher, Flynn, Hovey, Kilsby, Wheeler, Kirby-Lewis, Singhal, Smith, Whelan, Inglis, Ives, Nowak, Lobb, Begbie, Williams, Lwin, Woodward, Crosbie, Harrup, Pyszkowski, Gauden, Neville, 2015-10-16 08:28:35 AM
Background
The optimal use of bevacizumab in recurrent glioblastoma (GBM), including the choice of monotherapy or combination therapy, remains uncertain. The purpose of this study was to compare combination therapy with bevacizumab monotherapy.
Methods
This was a 2-part randomized phase 2 study. Eligibility criteria included recurrent GBM after radiotherapy and temozolomide, no other chemotherapy for GBM, and Eastern Cooperative Oncology Group performance status 0–2. The primary objective (Part 1) was to determine the effect of bevacizumab plus carboplatin versus bevacizumab monotherapy on progression-free survival (PFS) using modified Response Assessment in Neuro-Oncology criteria. Bevacizumab was given every 2 weeks, 10 mg/kg; and carboplatin every 4 weeks, (AUC 5). On progression, patients able to continue were randomized to continue or cease bevacizumab (Part 2). Secondary endpoints included objective radiological response rate (ORR), quality of life, toxicity, and overall survival (OS).
Results
One hundred twenty-two patients (median age, 55y) were enrolled to Part 1 from 18 Australian sites. Median follow-up was 32 months, and median on-treatment time was 3.3 months. Median PFS was 3.5 months for each arm (hazard ratio [HR]: 0.92, 95% CI: 0.64–1.33, P = .66). ORR was 14% (combination) versus 6% (monotherapy) (P = .18). Median OS was 6.9 (combination) versus 7.5 months (monotherapy) (HR: 1.18, 95% CI: 0.82–1.69, P = .38). The incidence of bevacizumab-related adverse events was similar to prior literature, with no new toxicity signals. Toxicities were higher in the combination arm. Part 2 data (n = 48) will be reported separately.
Conclusions
Adding carboplatin resulted in more toxicity without additional clinical benefit. Clinical outcomes in patients with recurrent GBM treated with bevacizumab were inferior to those in previously reported studies.
Clinical trials registration nr
ACTRN12610000915055.
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Harris, R. J., Cloughesy, T. F., Liau, L. M., Prins, R. M., Antonios, J. P., Li, D., Yong, W. H., Pope, W. B., Lai, A., Nghiemphu, P. L., Ellingson, B. M., 2015-10-16 08:28:35 AM
Background
Interstitial tissue acidosis resulting from abnormal perfusion and metabolism is a hallmark of cancer. The current study demonstrates that chemical exchange saturation transfer (CEST) MRI can be used as a noninvasive pH-weighted molecular imaging technique by targeting the chemical exchange between amine protons and protons in extracellular bulk water.
Methods
First, the sensitivity of amine CEST was validated in phantoms under a variety of conditions, including different magnetic field strengths, amino acid concentrations, and pH values. Amine CEST was compared with histology in both a preclinical GL261 intracranial glioma model at 7T and human patients at 3T. The association between physiologic and pH-weighted MRI was explored, along with the ability to predict time to progression to radiochemotherapy in 20 glioblastoma patients.
Results
z-Spectral asymmetry increased at 3 ppm (amine range) on CEST MRI with decreasing pH within the range observed in tumors for both 3T and 7T scanners. Lesions with acidic signatures showed active tumor and pseudopalisading tumor on histology and showed elevated FDOPA PET uptake, lactate on MR spectroscopy, and perfusion abnormalities. Patients with acidic lesions after surgery or stable/growing acidic lesions had a shorter time to progression following radiochemotherapy compared with patients with lesions demonstrating relatively low acidity (P < .001).
Conclusion
Results suggest pH-weighted MRI may provide new insight into brain tumor physiology beyond traditional imaging technologies.
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Wangaryattawanich, P., Hatami, M., Wang, J., Thomas, G., Flanders, A., Kirby, J., Wintermark, M., Huang, E. S., Bakhtiari, A. S., Luedi, M. M., Hashmi, S. S., Rubin, D. L., Chen, J. Y., Hwang, S. N., Freymann, J., Holder, C. A., Zinn, P. O., Colen, R. R., 2015-10-16 08:28:35 AM
Background
Despite an aggressive therapeutic approach, the prognosis for most patients with glioblastoma (GBM) remains poor. The aim of this study was to determine the significance of preoperative MRI variables, both quantitative and qualitative, with regard to overall and progression-free survival in GBM.
Methods
We retrospectively identified 94 untreated GBM patients from the Cancer Imaging Archive who had pretreatment MRI and corresponding patient outcomes and clinical information in The Cancer Genome Atlas. Qualitative imaging assessments were based on the Visually Accessible Rembrandt Images feature-set criteria. Volumetric parameters were obtained of the specific tumor components: contrast enhancement, necrosis, and edema/invasion. Cox regression was used to assess prognostic and survival significance of each image.
Results
Univariable Cox regression analysis demonstrated 10 imaging features and 2 clinical variables to be significantly associated with overall survival. Multivariable Cox regression analysis showed that tumor-enhancing volume (P = .03) and eloquent brain involvement (P < .001) were independent prognostic indicators of overall survival. In the multivariable Cox analysis of the volumetric features, the edema/invasion volume of more than 85 000 mm3 and the proportion of enhancing tumor were significantly correlated with higher mortality (Ps = .004 and .003, respectively).
Conclusions
Preoperative MRI parameters have a significant prognostic role in predicting survival in patients with GBM, thus making them useful for patient stratification and endpoint biomarkers in clinical trials.
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Boxerman, J. L., Schmainda, K. M., Zhang, Z., Barboriak, D. P., 2015-10-16 08:28:35 AM
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Pope, W. B., 2015-10-16 08:28:35 AM
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2015-10-16 08:28:35 AM
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World Neurosurgery
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2015-10-16 08:05:03 AM
Publication date: Available online 14 October 2015
Source:World Neurosurgery
Author(s): Hasan A. Zaidi, Aqib Zehri, Timothy R. Smith, Peter Nakaji, Edward R. Laws
Object The three-dimensional (3D) endoscope is a novel tool that provides stereoscopic vision and may allow for improved dexterity and safety during surgical resection of ventral skull base lesions. We describe here the cumulative experience available in the neurosurgical literature. Methods A PubMed literature review was performed to identify and analyze all studies pertaining to 3D endoscopic endonasal skull base surgery. ResultsTwenty-six articles were identified: 14 clinical articles, 5 simulated environment studies, 5 human cadaveric studies, and 2 expert opinions. Among clinical studies, a total of 262 patients were treated for the following 257 pathologies listed in the articles: 190 suprasellar/parasellar lesions (73.9%), 41 ventral skull base lesions (16.0%), 19 sinonasal pathologies (7.4%), and 7 CSF leak repairs (2.7%). Complication rates, operative time, length of hospital stay, and extent of tumor resection were equivalent between 2D and 3D endoscopy. However, all studies report that subjective depth perception and spatial orientation were markedly improved with 3D technology. Three studies (11.5%) concluded that there was no clinically significant surgical benefit in switching from 2D to 3D endoscopy. All cadaveric studies and expert opinions concluded that 3D endoscopy improved identification of key anatomical structures and was superior to 2D endoscopy. Simulated environment studies demonstrated that 3D endoscopy improves speed and accuracy of endonasal tasks, more so in novice surgeons.Conclusions Our findings suggest that this modality provides improved surgical dexterity by affording the surgeon with depth perception when manipulating tissue and maneuvering the endoscope in the endonasal corridor.
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2015-10-16 08:05:03 AM
Publication date: Available online 14 October 2015
Source:World Neurosurgery
Author(s): Yulius Hermanto, Yasushi Takagi, Akira Ishii, Kazumichi Yoshida, Takayuki Kikuchi, Takeshi Funaki, Yohei Mineharu, Susumu Miyamoto
Background Sox17 has emerged as an important factor in vascular remodeling, because of the potential linkage with Wnt/β catenin, notch and inflammatory pathway. Brain arteriovenous malformations (BAVMs) as an angiogenic and inflammatory disorder might possess an aberrant regulation of Sox17 associated pathway. Therefore, we sought to investigate the expression of Sox17 associated pathway in BAVMs. Methods Sixteen paraffin specimens of BAVMs nidus were analyzed by using immunohistochemical methods. Specimens were obtained from the patients during the surgical procedures. Results Expression of Sox17, Hey1, and β catenin were observed in all specimens. Large veins possessed distinct pattern of expression, thick walled had a stronger intensity, while thin walled had a weaker intensity of Sox17, Hey1, and β catenin (p < 0.001). The thick walled veins also had a higher expression of Sox 17, Hey1 and β catenin compared to large arteries (p < 0.05), furthermore the Hey1 and β catenin was also higher in the thick walled veins compared to brain microvessels (p< 0.01). In addition, the difference in expression of Sox17 associated pathway (Hey1 and β catenin) was also observed in medium and small arteries when compared to large arteries in BAVMs nidus and brain microvessels (p < 0.01). Conclusion Sox17 associated pathway was activated in the BAVMs nidus. Our results indicate that arterial identity is gained in the thick walled veins, this might reflect the process of arterialization of the veins as a resultant of hemodynamic stress. In addition, high expression of Sox17 associated pathway in medium and small arteries indicates that BAVMs vessels active intrinsically.
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2015-10-16 08:05:03 AM
Publication date: Available online 14 October 2015
Source:World Neurosurgery
Author(s): Tasuku Imai, Tomotaka Ohshima, Toshihisa Nishizawa, Shinji Shimato, Kyozo Kato
Background Preoperative endovascular embolization for hypervascular glioblastomas has not been established.Case Description We report the case of an extreme hypervascular glioblastoma mimicking an arteriovenous malformation that was successfully treated with preoperative embolization and subsequent removal. A 66-year-old man presented with progressive left hemiparesis and sensory aphasia. Cranial computed tomographic scans and magnetic resonance images revealed a left parietooccipital tumor with a ring enhancement. Digital subtraction angiography revealed an extreme high-flow arteriovenous shunt. The patient underwent presurgical endovascular embolization using n-butyl cyanoacrylate in a manner similar to embolization for arteriovenous malformations. The subsequent tumor removal was achieved with minimal blood loss. Conclusion This is the first reported case of presurgical embolization for a glioblastoma with a high-flow shunt. Embolization for a malignant tumor with a high-flow shunt, in a manner similar to embolization for arteriovenous malformations, is feasible and effective.
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2015-10-16 08:05:03 AM
Publication date: Available online 14 October 2015
Source:World Neurosurgery
Author(s): Zarina S. Ali, Jared M. Pisapia, Tracy S. Ma, Eric L. Zager, Gregory G. Heuer, Viviane Khoury
There are a variety of imaging modalities available for evaluation of peripheral nerves. Of these, ultrasonography (US) is often under-utilized. There are several advantages of this imaging modality, including its cost-effectiveness, time-efficient assessment of long segments of peripheral nerves, ability to perform dynamic maneuvers, lack of contraindications, portability, and non-invasiveness. As such, it can provide diagnostic information that cannot be obtained by electrophysiological or, in some cases, magnetic resonance imaging studies. Ideally, the neurosurgeon can utilize US as a diagnostic adjunct in the preoperative assessment of a patient with traumatic, neoplastic, infective, or compressive nerve injury. Perhaps its most unique use is in intraoperative surgical planning. Here, the authors present a brief description of normal US nerve anatomy followed by a description of the US appearance of pathological peripheral nerves due to trauma, tumor, infection, and entrapment.
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2015-10-16 08:05:03 AM
Publication date: Available online 13 October 2015
Source:World Neurosurgery
Author(s): Gioia Mione, Guillaume Pische, Valérie Wolff, Romain Tonnelet, Lisa Humbertjean, Sébastien Richard
Background Vision loss due to cerebral infarction during spinal surgery is less described. Intraoperative hypotension would be a leading cause. Patients with variation of the circle of Willis could be more prone to present stroke in this context but reports are lacking to sustain the theory. Bilateral occipital watershed ischemic strokes have never been described before. We report the case of a patient with a fetal origin of both posterior cerebral arteries (PCAs), presenting this particular anatomical stroke following lumbar laminectomy surgery for spinal stenosis during which intraoperative hypotension was observed. We discuss how this common anomaly associated with intraoperative hypotension could have promoted this serious complication. Case Description A 55-year-old man woke up with cortical blindness after he had undergone lumbar surgery during which a marked decrease in blood pressure had occurred. Magnetic resonance imaging revealed bilateral symmetric infarctions of the occipital lobes, in the distal territory of both PCAs, and smaller anterior watershed ischemic strokes, suggesting a hemodynamic mechanism. Extended investigations, including conventional angiography, failed to find any cause of stroke, but revealed bilateral fetal PCAs supplied by internal carotid arteries only. Two years later, the patient has not recovered and remains severely visually impaired. Conclusions The standing hypothesis would be posterior low flow infarctions resulting from intraoperative hypotension on a variation of the circle of Willis more prone to decrease in cerebral blood flow. Moreover, this case supports the hypothesis of vascular insufficiency due to intraoperative hypotension as cause of stroke during spinal surgery.
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2015-10-16 08:05:03 AM
Publication date: Available online 13 October 2015
Source:World Neurosurgery
Author(s): Bo Yuan Huang, Hua Zhang, Wen Jing Zong, Yan Hui Sun
Rosai-Dorfman disease (RDD) is a rare histioproliferative disorder that only occasionally involves the central nervous system (CNS). We presented the diagnosis and treatment of four patients with isolated spinal RDD. All the four patients were treated by total or subtotal surgical resection and none of them experienced recurrence. Histopathological examination showed a characteristic emperipolesis, the lymphocytes were engulfed in the S-100-protein-positive histiocytes with no expression of CD1a. Preoperative diagnosis of spinal RDD is still challenging because the lesion is usually a dura-based lesion that mimics a meningioma. Surgical resection is an effective treatment and radiotherapy, steroid and chemotherapy has not demonstrated reliable therapeutic efficiency.
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2015-10-16 08:05:03 AM
Publication date: Available online 13 October 2015
Source:World Neurosurgery
Author(s): Xiao-Jun Zeng, Da Li, Shu-Yu Hao, Liang Wang, Jie Tang, Xin-Ru Xiao, Guo-Lu Meng, Gui-Jun Jia, Li-Wei Zhang, Zhen Wu, Jun-Ting Zhang
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2015-10-16 08:05:03 AM
Publication date: Available online 13 October 2015
Source:World Neurosurgery
Author(s): Ryo Kitagawa, Hideki Murakami, Satoshi Kato, Mitsutoshi Nakada, Satoru Demura, Hiroyuki Tsuchiya
Background Paragangliomas are neuroendocrine tumors that originate from autonomic nervous system-associated paraganglia, and are rare tumor accounting for only 0.3% of all neoplasms. Malignant paragangliomas frequently spread to the skeleton. The authors present a case of malignant paraganglioma with bone metastases to the spine and cranium, and excellent local control achieved with en bloc tumor resection and reconstruction using frozen tumor-bearing bone for the sites of the metastases. Case The patient was a 61-year-old woman underwent retroperitoneal paraganglioma resection 12 years previously. Nine years after the primary surgery, she began to experience back pain. Magnetic resonance imaging revealed an isolated metastasis in T6, and the following evaluation detected another metastasis in the left temporal bone. We performed curative surgeries for the metastases, including total en bloc spondylectomy of T6, and partial craniectomy for the cranial metastasis, and spinal and cranial reconstruction using frozen tumor-bearing bone for the sites of the metastases. At the 24-months follow-up examination, bone fusion was achieved between the frozen bone and the adjacent healthy bone in the spine and cranium. At 36 months postoperatively, an asymptomatic metastatic lesion was found in the pelvis. Nevertheless, no local recurrences at the surgical sites were detected. Her quality of life and performance in activities of daily living were well preserved. To the author's knowledge, this is the first report to present a case of cranioplasty achieved using a liquid nitrogen frozen, tumor-bearing autologous bone flap in a single-stage operation.
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2015-10-16 08:05:03 AM
Publication date: Available online 13 October 2015
Source:World Neurosurgery
Author(s): Hidetoshi Matsukawa, Rokuya Tanikawa, Hiroyasu Kamiyama, Toshiyuki Tsuboi, Kosumo Noda, Nakao Ota, Shiro Miyata, Go Suzuki, Rihee Takeda, Sadahisa Tokuda
Background The revascularization technique has remained to be indispensable for complex aneurysms. However, risk factors for low-flow related ischemic complications (LRICs) and neurological worsening (NW) have been less well documented. We evaluated the risk factors for LRICs and NW in 67 patients treated with extracranial to intracranial (EC-IC) bypass graft using radial artery or saphenous vein graft for complex internal carotid artery (ICA) aneurysm with ICA occlusion. Methods Intraoperative middle cerebral artery pressure (MCAP) by backup superficial temporal artery to middle cerebral artery bypass was measured. The MCAP ratio (MCAPR) was the ratio of the MCAP after release of the graft bypass to the initial MCAP. LRICs were defined as new neurological deficits and ipsilateral cerebral blood flow reduction in single photon emission computed tomography. Early and late NW were defined as an increase in 1 or more modified Rankin Scale at discharge and at the 12-month follow-up examination. Results During a median follow-up period of 13.3 months, LRICs were observed in 7 patients (10%). The Cox proportional hazards model showed a MCAPR ≦0.80 was significantly related to LRICs. Multivariate logistic regression analysis revealed perforating artery ischemia was significantly associated with early NW (n=13, 19%) and late NW (n=7, 13%). It also showed that LRICs were also significantly related to late NW. Conclusions The present study showed that regardless of the graft type, the MCAPR was associated with LRICs, which were related to late NW in patients with complex ICA aneurysms treated by EC-IC high-flow bypass graft.
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2015-10-16 08:05:03 AM
Publication date: Available online 13 October 2015
Source:World Neurosurgery
Author(s): Masahiro Indo, Soichi Oya, Toru Matsui
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2015-10-16 08:05:03 AM
Publication date: Available online 13 October 2015
Source:World Neurosurgery
Author(s): Richard B. Tenser
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2015-10-16 08:05:03 AM
Publication date: Available online 13 October 2015
Source:World Neurosurgery
Author(s): Shoji Yokobori, Masahiro Yamaguchi, Yutaka Igarashi, Kohei Hironaka, Hidetaka Onda, Kentaro Kuwamoto, Takashi Araki, Akira Fuse, Hiroyuki Yokota
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2015-10-16 08:05:03 AM
Publication date: Available online 13 October 2015
Source:World Neurosurgery
Author(s): Paul F. Koch, Tamara Fierst, Austin J. Heuer, Mariarita Santi, Gregory G. Heuer
Background Infantile myofibroma/myofibromatosis (IM/M) is a myofibroblastic proliferative disorder often seen in infants and children. IM/M can result in congenital tumors of the head and neck and may occasionally present to the neurosurgeon. Case Description We report a case of a solitary ruptured myofibroma of the head in a newborn patient. The lesion was initially suggestive of encephalocele. We describe the presentation and management of this patient, including relevant imaging, histopathological evaluation and surgical technique. We subsequently review the literature of IM/M of the head and neck, highlighting the three forms of the condition, each requiring a distinct management strategy. Conclusion While this tumor rarely presents to the neurosurgeon, it may do so in the process of ruling out other more dangerous conditions. It is therefore important to consider this diagnosis in masses that occur in the head and neck of newborns.
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2015-10-16 08:05:03 AM
Publication date: Available online 13 October 2015
Source:World Neurosurgery
Author(s): Fuxin Lin, Jun Wu, Bing Zhao, Xianzeng Tong, Zhen Jin, Yong Cao, Shuo Wang
Objective The relationship between preoperative functional findings, derived from functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI), and surgical outcomes in patients with motor cortical arteriovenous malformations (AVMs) has not been determined. The aim of this study was to determine the relationship between preoperative functional findings and surgical outcomes in patients with motor cortical AVM.Materials and Methods Fifteen patients with AVM involving precentral knob and/or paracentral lobule were reviewed. Each involved motor function was examined as an independent object. Preoperative functional findings included cortical reorganization, activation around the nidus, corticospinal tract (CST) reorganization, nidus involving the CST and the involved level of CST. The relationship between preoperative functional findings and surgical outcomes was statistically analyzed. A muscle strength≤grade 3 was defined as a poor outcome after surgery, and a muscle strength≥grade 4 was defined as a good outcome. Results Eighteen objects were created and analyzed. Cortical reorganization (p=1.000) was not correlated with surgical outcomes. However, nidus involving the CST was significantly associated with poor short-term outcomes (1week after surgery) (p=0.028) and permanent muscle strength deficit (p=0.042). Most of the objects had good outcomes (16/18, 88.9%) at 6 months after surgery (long-term outcomes). Only one patient with CST ruptured at the corona radiata level and one patient who suffered from postoperative hemorrhage obtained poor long-term outcomes. Conclusions Nidus involving the CST and the involved level of the CST, rather than cortical reorganization, may be associated with surgical outcomes in patients with motor cortical AVM.
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2015-10-16 08:05:03 AM
Publication date: Available online 13 October 2015
Source:World Neurosurgery
Author(s): Dale Ding, Zhiyuan Xu, Han-Hsun Shih, Robert M. Starke, Chun-Po Yen, Jason P. Sheehan
Objective Incomplete microsurgical resection of cerebral arteriovenous malformations (AVM) occurs uncommonly. However, such patients harboring postoperative residual nidi remain exposed to the risk of AVM hemorrhage and are, therefore, reasonable candidates for further intervention. The goals of this retrospective case-control study are to analyze the radiosurgery outcomes for partially resected AVMs and determine the effect of prior resection on AVM radiosurgery outcomes. Methods We evaluated a prospective database of AVM patients treated with radiosurgery from 1989-2013. Previously resected AVMs with radiologic follow-up ≥2 years or nidus obliteration were selected for analysis and matched, in a 1:1 fashion and blinded to outcome, to previously unresected AVMs. Statistical analyses were performed to assess relationship between prior resection and AVM radiosurgery outcomes. Results The matching process yielded 88 patients in each of the previously resected and unresected AVM cohorts. In the resected AVM cohort, the actuarial AVM obliteration rates at 3 and 5 years were 47% and 75%, respectively; the rates of radiologic and symptomatic radiation-induced changes (RIC) were 10% and 3%, respectively; and the annual post-radiosurgery hemorrhage risk was 1.1%. The lack of prior AVM resection (P<0.001) and superficial AVM location (P=0.009) were independent predictors of radiologic RIC. The actuarial rates of obliteration (P=0.849) and post-radiosurgery hemorrhage (P=0.548) were not significantly different between the resected and unresected AVM cohorts. Conclusions Radiosurgery affords a reasonable risk to benefit profile for incompletely resected AVMs. For those with a small volume residual nidus after resection, radiosurgery should be considered an effective alternative to repeat resection.
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2015-10-16 08:05:03 AM
Publication date: Available online 13 October 2015
Source:World Neurosurgery
Author(s): Xi Chen, Yu Yao, Liang-Fu Zhou
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2015-10-16 08:05:03 AM
Publication date: Available online 13 October 2015
Source:World Neurosurgery
Author(s): Kee B. Park, Vycheth Iv
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2015-10-16 08:05:03 AM
Publication date: Available online 13 October 2015
Source:World Neurosurgery
Author(s): Dirk De Ridder, Mary Jane Sime, Peter Taylor, Tomas Menovsky, Sven Vanneste
Background Microvascular decompression surgery is standard neurosurgical practice for treating trigeminal neuralgia and hemifacial spasm. Most other cranial nerves have been decompressed for paroxysmal intermittent hyperactivity of the affected cranial nerve or in very longstanding compressions to treat cranial nerve hypo-functioning. Case description We here describe a case of intermittent paroxysmal unilateral phosphenes (i.e., light flashes) associated with worsening visual field defects. Magnetic resonance imaging (MRI) demonstrated a sandwiched optic nerve/chiasm between an inferior compression of the internal carotid artery (ICA) and a superior compression of the anterior communicating artery (ACoA). He was successfully treated by a microvascular decompression and anterior clinoidectomy plus optic canal unroofing. Conclusion This case report adds to the few previous case reports in combining 2 previously described techniques, i.e. microvascular decompression and anterior clinoidectomy plus optic canal unroofing.
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2015-10-16 08:05:03 AM
Publication date: Available online 13 October 2015
Source:World Neurosurgery
Author(s): Felix Hendrik Pahl, Eduardo de Arnaldo Silva Vellutini, Alberto Carlos Capel Cardoso, Matheus Fernandes de Oliveira
Background Giant aneurysms arising from the vertebral artery (VA) are often associated with thrombosis and present as mass lesions with slow progression of symptoms and signs. A consensus is still to be established on the underlying growth mechanisms and surgical management of thrombosed giant aneurysms of the vertebral artery. Clinical presentation Here we report the case of a 54-year-old man who searched neurosurgical care after 3 months of progressive cervical axial pain. He underwent cervical magnetic resonance imaging (MRI) and cerebral angiography, which revealed a giant VA aneurysm with thrombosed component. After failure of proximal and distal endovascular treatment, it was decided to perform surgical approach, which revealed a markedly developed vasa vasorum in aneurismal walls, raising the possibility of intraaneurismal nutrition from vasa vasorum. Patient recovered progressively and almost completely after surgery. Discussion and conclusionsAnother report have already described the case of a 58-year-old woman harboring a partially thrombosed giant aneurysm of VA. Interestingly, at the time of resection, a marked development of vasa vasorum on the occluded VA and the neck of the aneurysm was noted. We highlight the need to comprehend vasa vasorum as potential sources for aneurismal growth.
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2015-10-16 08:05:03 AM
Publication date: Available online 11 October 2015
Source:World Neurosurgery
Author(s): I.A. Sbeih, M.Y. Asad
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2015-10-16 08:05:03 AM
Publication date: Available online 9 October 2015
Source:World Neurosurgery
Author(s): Jody Filippo Capitanio, Alice Venier, Lucio Aniello Mazzeo, Lina Raffaella Barzaghi, Stefania Acerno, Pietro Mortini
Background Exposure to magnetic fields may alter the settings of programmable ventriculo-peritoneal shunt valves or even cause permanent damages to these devices. There are little information about this topic, none on live patients. Objective To investigate the effects of 1,5-Tesla MRI on Hakim-Codman ® (HC®) pressure-programmable valves implanted in our hospital. Methods A single-center prospective study to assess the rate of perturbations of HC® programmable valve implanted. One-hundred consecutive patients implanted for different clinical reasons between 2008 and 2012 were examined. A conventional skull x-ray before and after a Standard MRI on 1,5 Tesla (T). We face pre and post results, analyze modification rate and verify eventual damages to the implanted devices. Results Implanted HC® valves are extremely handy and durable even if they are likely to change often due to the exposure to magnetic fields. None of the patients complains of heating effects. Oscillations range from 10 to 30 mmH20 with a case that reached 50 mmH20 and one that reached 60mmH20.Global alteration rate was 40%; 10 patients (10%) experienced a 10mmH20 changes; 14 patients (14%) 20mmH20; 6 patients (6%); 30mmH20; 8 patients (8%) 40mmH20, 1 patient 50mmH20 and 1 patient 60 mmH20. Conclusions HC® valves presented a variable perturbation rate with an alteration rate of 40% by 1,5-T MRI. We haven't observed malfunctioning hardware after magnetic influnce. We claim a cranial x-ray immediately afetr MRI because of a high risk (40%) of decalibration especially in patients with low ventricles compliance.
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2015-10-16 08:05:03 AM
Publication date: Available online 9 October 2015
Source:World Neurosurgery
Author(s): Yoshikazu Ogawa, Kenichi Sato, Yasushi Matsumoto, Teiji Tominaga
Background Giant pituitary adenomas carry higher surgical risks despite recent advances in microsurgical and/or endoscopic surgery, and postoperative acute catastrophic changes without major vessel disturbance are still extremely difficult to predict, may manifest as postoperative pituitary apoplexy, and are associated with very poor outcomes. Methods Eight males and four females aged 31 to 72 years (mean 50.7 years) with giant pituitary adenomas underwent preoperative investigation of fine angioarchitecture using C-arm cone-beam computed tomography with a flat-panel detector. Angiographical findings were used to decide the surgical routes, and compared with clinical outcome. Results Feeding arteries were verified in 10 of 12 patients, whereas no feeding arteries were evident in 2 patients. The patients were divided into the faint tumor staining group and the significant staining group, which was re-confirmed by region of interest analysis. The former group had faint supply from the ipsilateral superior hypophyseal arteries and meningohypophyseal trunk, and the latter group had significant supply from the meningohypophyseal and inferolateral trunks, which passed centrifugally from the inferoposterior pole of the tumor. All patients were treated through the extended transsphenoidal approach. Intraoperative bleeding was significantly greater in the latter group (p=0.013). All patients had improvement of neurological deficit, and were released from the intensive care within a few days. Conclusions Major blood supply of giant pituitary adenomas originates from branches of the infraclinoidal portion of the internal carotid artery, different from normal anterior pituitary gland. Surgical route should depend not only on tumor shape and extension but on feeding systems.
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2015-10-16 08:05:03 AM
Publication date: Available online 9 October 2015
Source:World Neurosurgery
Author(s): Behzad Eftekhar
Background Neuronavigation is an established technology in neurosurgery. In parts of the world and in certain circumstances that neuronavigation is not easily available or affordable, alternative techniques maybe considered.Objective An app to assist scalp localization of superficial supratentorial lesions has been introduced and its accuracy compared with established neuronavigation systems. Methods Sina, is a simple smartphone app that overlaps the transparent patients' CT/MRI images on the background camera. How to use Sina intraoperatively is described. The app was used for scalp localization of the center of the lesions in 11 patients with supratentorial pathologies less than 3 cm in longest diameter and less than two cm from the cortex. After localization of the lesion using Sina, the center of the lesion was marked on the scalp using standard neuronavigation systems and the deviations were measured. Results Implementation of Sina for intraoperative scalp localization is simple and practical . The center of the lesions localized by Sina was 10.2±2 mm different from localization done by standard neuronavigation systems. Conclusion In certain circumstances that neuronavigation is not easily available or affordable, Sina can be helpful for scalp localization and pre-operative planning of the incision for selected supratentorial pathologies.
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2015-10-16 08:05:03 AM
Publication date: Available online 9 October 2015
Source:World Neurosurgery
Author(s): Wellingson da Silva Paiva, Almir Ferreira de Andrade, Manoel Jacobsen Teixeira
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2015-10-16 08:05:03 AM
Publication date: Available online 9 October 2015
Source:World Neurosurgery
Author(s): Ran Harel
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2015-10-16 08:05:03 AM
Publication date: Available online 9 October 2015
Source:World Neurosurgery
Author(s): Seyed Amirhossein Javadi
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2015-10-16 08:05:03 AM
Publication date: Available online 8 October 2015
Source:World Neurosurgery
Author(s): Jennifer B. Nabaweesi, Peter Kithikii Kitunguu, Julius G. Kiboi
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2015-10-16 08:05:03 AM
Publication date: Available online 3 October 2015
Source:World Neurosurgery
Author(s): Apio Antunes
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2015-10-16 08:05:03 AM
Publication date: Available online 3 October 2015
Source:World Neurosurgery
Author(s): Kaith K. Almefty, Robert F. Spetzler
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2015-10-16 08:05:03 AM
Publication date: Available online 3 October 2015
Source:World Neurosurgery
Author(s): Premanand Ramani
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2015-10-16 08:05:03 AM
Publication date: Available online 3 October 2015
Source:World Neurosurgery
Author(s): Geng Zhou, Ming Su, Yue-Qi Zhu, Ming-Hua Li
Background To evaluate the efficacy of flow-diverting devices (FDDs) used in the treatment for intracranial aneurysms (IAs), we performed a meta-analysis of published literature on FDDs. Methods A systematic electronic database search was conducted using MEDLINE, PubMed, Springer, and EBSCO for all accessible articles on FDDs published until December 2014. Abstracts, full-text manuscripts, and the reference lists of retrieved articles were analyzed. Random effects meta-analysis was used to pool the occlusion rate outcomes across studies. ResultsFifty-nine studies containing efficacy data on 2263 patients with more than 2493 treated aneurysms were included in the analysis. The overall complete occlusion rate was 82.5% (95% CI, 78.8%–86%) across studies. The success rate of FDD implantation was 97.4% (95% CI, 95.4%–99.4%). The occlusion rate for anterior circulation aneurysms was 83.3% (95% CI, 71.2%–95.4%); with regard to complete occlusion, the odds ratio for anterior circulation aneurysms was significantly higher than that of posterior circulation IAs (odds ratio, 1.93; 95% CI, 1.00–3.73). Conclusions FDDs have high technical success rates in the management of IAs. Additional studies on well-designed multicenter randomized controlled trials will be required to validate the findings of the present study and to identify the best therapeutic strategy for IAs depending on their size, location, and characteristics.
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2015-10-16 08:05:03 AM
Publication date: Available online 2 October 2015
Source:World Neurosurgery
Author(s): Naotaka Iwamoto, Kyongsong Kim, Toyohiko Isu, Yasuhiro Chiba, Daijiro Morimoto, Masanori Isobe
Study Design Retrospective analysis of prospectively collected data. Object The diagnosis of common peroneal nerve entrapment neuropathy (CPNEN) is based on clinical symptoms and nerve conduction studies. However, nerve conduction studies may not detect abnormalities. Under the hypothesis that repetitive plantar flexion that loads the peroneal nerve (PN) at the entrapment point without lumbar loading would be a useful CPNEN provocation test we evaluated the repetitive plantar flexion (RPF) test as an adjunct diagnostic tool for CPNEN.Methods Our study population consisted of 18 consecutive patients whose ipsilateral CPNEN improved significantly after PN neurolysis. Using repetitive ankle plantar flexion as a CPNEN provocation test, results were recorded as positive when it elicited numbness and/or pain in the affected area of the PN. Results The RPF test induced symptoms on all affected sides in the course of 57.4 sec (range 14 - 120 sec). In 3 patients it induced numbness in the affected area of the PN in the normal leg. ROC analysis showed that the diagnostic sensitivity and accuracy of the test were 94.4% each. The suggested cut-off point was 110 sec and the area under the ROC curve was 0.97 (95% confidence intervals, 0.93 - 1.02). The positive and the negative predictive value was 89.5% and 94.1%, respectively. Conclusions Our simple RPF test elicited the symptoms of CPNEN and our provocation test helped to identify dynamic PN entrapment neuropathy as the origin of intermittent claudication.
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2015-10-16 08:05:03 AM
Publication date: Available online 2 October 2015
Source:World Neurosurgery
Author(s): Samir Alkabie, Andrew J. Boileau
Background Traumatic spinal cord injury (SCI) is a devastating neurological entity characterized by a primary insult followed by a secondary pathological cascade that propagates further injury. Hypothermia has an established clinical role in preventing SCI after cardiac arrest and thoracoabdominal aortic aneurysm repair, yet its emergence as a potential neuroprotectant after spinal cord trauma remains experimental. There are currently no pharmacological interventions available to prevent secondary mechanisms of injury after spinal cord trauma.Methods Systematic review of literature. Results Experimental studies demonstrated that hypothermia diminishes secondary pathomechanisms, such as ischemia, oxidative stress, apoptosis, inflammation and edema. Early onset and longer durations of hypothermia as well as concomitant steroids or neural stem cell engraftment combined with hypothermia appear to improve functional and histological outcomes in animal models of spinal cord trauma. Recent clinical studies provide evidence that localized and systemic hypothermia may be applied safely and efficaciously in patients with severe acute SCI. Randomized clinical trials are needed to better evaluate optimal cooling parameters and the effectiveness of hypothermia after traumatic SCI. Conclusion Although variability exists in the literature, therapeutic hypothermia most likely confers neuroprotection after spinal cord trauma by diminishing the destructive secondary cascade. The available clinical data suggests that regional and systemic hypothermia is a relatively safe and feasible initial treatment modality for acute SCI patients, when combined with surgical decompression/stabilization with or without steroids. However, establishing a clinical role for therapeutic hypothermia after spinal cord trauma will invariably depend on future well-designed, multicentered, randomized, controlled clinical trial data.
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2015-10-16 08:05:03 AM
Publication date: Available online 2 October 2015
Source:World Neurosurgery
Author(s): Erez Nossek, Zvi Ram
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2015-10-16 08:05:03 AM
Publication date: Available online 2 October 2015
Source:World Neurosurgery
Author(s): M. Pierson, P.V. Birinyi, S. Bhimireddy, J.R. Coppens
Objective Decompressive craniectomy is an established treatment for malignant intracranial hypertension. Cranioplasty is performed once cerebral swelling has resolved. Complications include infection, postoperative fluid collections, hematoma, reoperation, and seizures. The authors review their experience using a double layer technique during craniectomy using a collagen matrix onlay dural substitute and expanded polytetrafluoroethylene (ePTFE) for antiadhesive properties during cranioplasty. Methods Retrospective chart review of 39 consecutive patients who underwent craniectomy with placement of collagen matrix dural onlay and ePTFE and subsequent cranioplasty. Demographic data, size of craniectomy defect, estimated blood loss (EBL), operative time, time between operations, presence of dural tackups, and postoperative complications were analyzed. Results Mean operative time was 132 minutes and EBL was 112 ml. Overall complication rate was 25.6% and no mortality was encountered. Nine patients had postoperative fluid collections measuring 10 mm or greater in thickness and/or 5 mm of midline shift. Two patients required reoperation for these collections. Two patients developed infections requiring bone flap removal. Three patients developed seizures after cranioplasty. Five patients required shunt placement for hydrocephalus. Conclusion Our dual layer closure technique at time of decompressive craniectomy carries a similar reduction in operative time and estimated blood loss when compared to cranioplasty series with other antiadhesives present. The technique described enables easy dissection of the musculocutaneous flap from the dural plane during cranioplasty and increases the safety of the operation.
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2015-10-16 08:05:03 AM
Publication date: Available online 2 October 2015
Source:World Neurosurgery
Author(s): Kern H. Guppy, Harsimran S. Brara, Johannes A. Bernbeck
Background Several studies have shown excellent fusion rates in occipitocervical (OC) fusions, but very little is reported on mortality and reoperation rates in elderly patients. Our paper reports these rates in elderly patients from a national spine registry with > 2-year followup period. Methods Using data from a spine implant registry developed at a large integrated healthcare system (Kaiser Permanente), elderly patients (age ≥ 65) with instrumented OC fusions between 1/1/2009 and 9/30/2011 were identified. Patients' demographics were extracted from the registry. From chart review, the types of hardware and bone graft used, as well as mortality and reoperations rates were noted. Results Forty-seven patients with OC fusions were identified. Six patients had reoperations related to their fusions. Two occurred in the same patient which resulted in 14.9% reoperation rate. There were a total of 13 deaths (27.7%), with 7 occurring within 3 months, but only 4 (8.5%) related to the procedure. Bone Morphogenetic Protein (BMP) was used in 29 patients (85.3%, 29/34). All cases used occipital plates with rods and screws. There was one nonunion. Conclusions Mortality rate was 27.7% and the reoperations rate was 14.9 % for patients who underwent occipitocervical fusions with age greater than 65 years and were observed for > 2-years. These numbers are much higher than in younger patients, but reflect higher mortality due to their co-morbidities and from progression of their disease for cases of metastasis to the spine.
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2015-10-16 08:05:03 AM
Publication date: Available online 2 October 2015
Source:World Neurosurgery
Author(s): Stephen Honeybul, Courtney Janzen, Kate Kruger, Kwok M. Ho
Objective To determine whether there was a measureable change in neurological function following cranioplastyMethods This is a prospective single surgeon, single centre study. Fifty patients who required a cranioplasty procedure were neurologically assessed within 72 hours before and 7 days after surgery. The assessment tools were the functional independence measure (FIM) and the Cognitive assessment report (COGNISTAT). The scores for both assessments were calculated and then compared before and after surgery. Results FIM assessment was performed on all fifty patients and a Cognistat assessment was performed on forty seven patients. Most improvements were seen in the Cognistat scores however there appeared to be no specific areas in which there was consistent improvement. There were substantial improvements in the Cognistat assessment in nine patients. One patient had a much-improved FIM assessment (improved from 18 to 34), but a Cognistat assessment was not possible due to poor neurological function. These results suggested that improvements after cranioplasty were more likely to occur in the domain of cognitive function than motor function, although overall these results did not reach statistically significance. Bifrontal (versus unilateral) cranioplasty, timing between decompression and cranioplasty and age of the patients did not appear to affect the postoperative FIM scores, after adjusting for preoperative FIM scores and surgical complications. Conclusions A small but significant number of patients appear to improve clinically following cranioplasty. Neurological susceptibility to a skull defect may be more common than had been previously appreciated.
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2015-10-16 08:05:03 AM
Publication date: October 2015
Source:World Neurosurgery, Volume 84, Issue 4
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2015-10-16 08:05:03 AM
Publication date: October 2015
Source:World Neurosurgery, Volume 84, Issue 4
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2015-10-16 08:05:03 AM
Publication date: October 2015
Source:World Neurosurgery, Volume 84, Issue 4
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2015-10-16 08:05:03 AM
Publication date: October 2015
Source:World Neurosurgery, Volume 84, Issue 4
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2015-10-16 08:05:03 AM
Publication date: October 2015
Source:World Neurosurgery, Volume 84, Issue 4
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2015-10-16 08:05:03 AM
Publication date: October 2015
Source:World Neurosurgery, Volume 84, Issue 4
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2015-10-16 08:05:03 AM
Publication date: October 2015
Source:World Neurosurgery, Volume 84, Issue 4
Author(s): Ed Benzel
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2015-10-16 08:05:03 AM
Publication date: October 2015
Source:World Neurosurgery, Volume 84, Issue 4
Author(s): Rami James N. Aoun, Youssef J. Hamade, Samer G. Zammar, Naresh P. Patel, Bernard R. Bendok
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2015-10-16 08:05:03 AM
Publication date: October 2015
Source:World Neurosurgery, Volume 84, Issue 4
Author(s): Evgenii Belykh, Morgan Giers, Liudmila Bardonova, Nicholas Theodore, Mark Preul, Vadim Byvaltsev
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2015-10-16 08:05:03 AM
Publication date: October 2015
Source:World Neurosurgery, Volume 84, Issue 4
Author(s): M. Yashar S. Kalani, Felipe C. Albuquerque
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2015-10-16 08:05:03 AM
Publication date: October 2015
Source:World Neurosurgery, Volume 84, Issue 4
Author(s): Jay D. Turner, Corey T. Walker, Gregory M. Mundis, U. Kumar Kakarla
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2015-10-16 08:05:03 AM
Publication date: October 2015
Source:World Neurosurgery, Volume 84, Issue 4
Author(s): Erez Nossek, Zvi Ram
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2015-10-16 08:05:03 AM
Publication date: October 2015
Source:World Neurosurgery, Volume 84, Issue 4
Author(s): Leonidas M. Quintana
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FeedaMail: Microbiology via ola Kala on Inoreader
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Simple detection of Pythium irregulare using loop-mediated isothermal amplification assay
Pythium irregulare is an important soil-borne pathogen that causes seed, stem and root rot, and seedling damping-off in various crops. Here, we have developed a rapid and reliable approach for detecting the pathogen using loop-mediated isothermal amplification (LAMP) in combination with primers designed from the sequences of the P. irregulare ribosomal DNA internal transcribed spacer region. The specificity of the primers for P. irregulare was tested using 50 isolates of 40 Pythium species, 11 Phytophthora isolates and 8 isolates of 7 other soil-borne pathogens. The assay showed that the limit of sensitivity of the LAMP method was 100 fg of pure DNA, a similar level to that of a polymerase chain reaction. LAMP detected P. irregulare from the supernatant after mixing culture medium (template DNA source) with distilled water. Similarly, positive results were obtained using a 'Plant-LAMP' method applied to a suspension rotted roots in water. A 'Bait-LAMP' method using the supernatant of autoclaved perilla seeds incubated in a soil/water mixture for 1 week at 25°C successfully detected P. irregulare from the soil. The LAMP assay described in this study is therefore a simple and effective way for practical detection of P. irregulare.
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Characterizing and optimizing magnetosome production of Magnetospirillum sp. XM-1 isolated from Xi'an City Moat, China
Pure culture of magnetotactic bacteria is desirable to understand their physiology, evolution and biomineralization. Here, we report a new strain Magnetospirillum sp. XM-1 that was recently isolated and cultivated from the eutrophic city moat of Xi'an, China. Magnetosome biomineralization, crystallographic and magnetic properties of XM-1 were characterized by using a combination of transmission electron microscopy and rock magnetic methods. Cell growth and magnetite production was optimized by response surface methodology. We found that the Magnetospirillum strain XM-1 is different from the model strain Magnetospirillum magneticum AMB-1 in terms of magnetite magnetosomes, optimal growth temperature and nutrient requirements. Sodium succinate, sodium nitrate and ferric citrate are the three most significant factors associated with the optimization of cell growth and magnetosome production for XM-1.
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The small RNA Spot 42 regulates the expression of the type III secretion system 1 (T3SS1) chaperone protein VP1682 in Vibrio parahaemolyticus
The cytotoxicity of Vibrio parahaemolyticus has been related to the type III secretion system 1 effector protein VP1680, which is secreted and translocated into host cells with the help of the specific chaperone protein, VP1682. This study sought to confirm the in silico analysis, which predicted that a small regulatory RNA (Spot 42) could base pair with the region encompassing the ribosomal-binding site and initiation codon of the vp1682 mRNA. Electrophoresis mobility shift assays indicated that Spot 42 could bind to the vp1682 mRNA with the help of Hfq. Consistent with these results, the translation of the vp1682 mRNA was inhibited when both Hfq and Spot 42 were added to the in vitro translation reaction. The cytotoxic activity against infected Caco-2 cells was significantly increased in the Spot 42 deletion mutant ( spf) at 4 h after infection as compared with the parental strain. Additionally, we observed that both VP1682 and VP1680 were more highly expressed in spf mutants than in the parental strain. These results indicate that Spot 42 post-transcriptionally regulates the expression of VP1682 in V. parahaemolyticus, which contributes to cytotoxicity in vivo.
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Variation in antigen-antibody affinity among serotypes of Salmonella O4 serogroup, determined using specific antisera
Serotyping is widely used for typing Salmonella during surveillance, and depends on determining the lipopolysaccharide (LPS) O-antigen and the flagellar protein (H-antigens) components. As the O-antigen is highly variable, and structurally unique to each serotype, we investigated the binding affinities of LPS from Salmonella serotypes of O4 serogroup with specific anti-antigen serum via immunoblot and enzyme-linked immunosorbent assays. Since the serotypes from O4 serogroup also express the O-antigen factor 12, O12 antiserum was also used for the analysis. LPS from the different serotypes showed different binding affinities with the antisera. Therefore, based on the antigen-antibody affinity, a modified agglutination assay was carried out by using O4 and O12 antisera. Although serotypes from O4 serogroup have the common O-antigen factors 4 and 12, the analysis showed that the degree of agglutination reaction is different for each of the serotypes. We suggest that Salmonella serogroup O4 serotypes exhibit different binding affinities with specific antisera despite the presence of common O-antigen factors 4 and 12.
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Stable symbionts across the HMA-LMA dichotomy: low seasonal and interannual variation in sponge-associated bacteria from taxonomically diverse hosts
Marine sponges host bacterial communities with important ecological and economic roles in nature and society, yet these benefits depend largely on the stability of host–symbiont interactions and their susceptibility to changing environmental conditions. Here, we investigated the temporal stability of complex host–microbe symbioses in a temperate, seasonal environment over three years, targeting sponges across a range of symbiont density (high and low microbial abundance, HMA and LMA) and host taxonomy (six orders). Symbiont profiling by terminal restriction fragment length polymorphism analysis of 16S rRNA gene sequences revealed that bacterial communities in all sponges exhibited a high degree of host specificity, low seasonal dynamics and low interannual variability: results that represent an emerging trend in the field of sponge microbiology and contrast sharply with the seasonal dynamics of free-living bacterioplankton. Further, HMA sponges hosted more diverse, even and similar symbiont communities than LMA sponges and these differences in community structure extended to core members of the microbiome. Together, these findings show clear distinctions in symbiont structure between HMA and LMA sponges while resolving notable similarities in their stability over seasonal and inter-annual scales, thus providing insight into the ecological consequences of the HMA-LMA dichotomy and the temporal stability of complex host–microbe symbioses.
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Construction and pilot screening of a signature-tagged mutant library of Sinorhizobium fredii
Abstract
Sinorhizobium fredii is well known for its ability to establish symbiosis with diverse legumes such as Glycine max (soybean, determinate nodules) and Cajanus cajan (pigeon pea, indeterminate nodules). In order to make screening of S. fredii genes related to symbiosis cost-effective, we constructed a large Tn 5 insertion mutant library of S. fredii CCBAU45436 using the signature-tagged mutagenesis (STM) technique. This STM library contains a total of 25,500 independent mutants distributed in 17 sublibraries tagged by corresponding distinct DNA bar-code sequences. After the pilot screening of 255 mutants in 15 batches, Tag85-4, Tag4-17, Tag4-11 and Tag10-13 were found to have attenuated competitiveness (0–30 % in nodule occupation) compared to the wild-type strain when inoculated on soybean. Further characterization of these mutants suggests that Tag4-11 (a pyrC mutant) and Tag10-13 (a nrdJ mutant) are defective in establishing symbiosis with soybean. The pyrC mutant induced uninfected pseudonodules while the nrdJ mutant formed significantly more nodules containing bacteroids with poor persistence ability. When these two mutants were tested on pigeon pea, host-specific symbiotic defects were found. These results demonstrated the STM library as a valuable resource for identifying S. fredii genes relevant to symbiosis.
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Cephalalgia -- Preview Articles
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Coppola, G., Bracaglia, M., Di Lenola, D., Iacovelli, E., Di Lorenzo, C., Serrao, M., Evangelista, M., Parisi, V., Schoenen, J., Pierelli, F., 2015-10-07 07:57:36 AM
Background
We studied lateral inhibition in the somatosensory cortex of migraineurs during and between attacks, and searched for correlations with thalamocortical activity and clinical features.
Participants and methods
Somatosensory evoked potentials (SSEP) were obtained by electrical stimulation of the right median (M) or ulnar (U) nerves at the wrist or by simultaneous stimulation of both nerves (MU) in 41 migraine without aura patients, 24 between (MO), 17 during attacks, and in 17 healthy volunteers (HVs). We determined the percentage of lateral inhibition of the N20–P25 component by using the formula [(100)–MU/(M + U)*100]. We also studied high-frequency oscillations (HFOs) reflecting thalamocortical activation.
Results
In migraine, both lateral inhibition (MO 27.9% vs HVs 40.2%; p = 0.009) and thalamocortical activity (MO 0.5 vs HVs 0.7; p = 0.02) were reduced between attacks, but not during. In MO patients, the percentage of lateral inhibition negatively correlated with days elapsed since the last migraine attack (r = –0.510, p = 0.01), monthly attack duration (r = –0.469, p = 0.02) and severity (r = –0.443, p = 0.03), but positively with thalamocortical activity (r = –0.463, p = 0.02).
Conclusions
We hypothesize that abnormal migraine cycle-dependent dynamics of connectivity between subcortical and cortical excitation/inhibition networks may contribute to clinical features of MO and recurrence of attacks.
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Lebedeva, E. R., Kobzeva, N. R., Gilev, D., Olesen, J., 2015-10-07 07:57:36 AM
Background
The aim of our study was to estimate the one-year prevalence of primary headache disorders in three different social groups using the third edition beta of the International Classification of Headache Disorders (ICHD-3 beta).
Material and methods
The study population included a total of 3124 participants: 1042 students (719 females, 323 males, mean age 20.6, age range 17–40), 1075 workers (146 females, 929 males, mean age 40.4, age range 21–67) and 1007 blood donors (484 females, 523 males, mean age 34.1, age range 18–64). We used a semi-structured, validated face-to-face interview.
Results
The age-adjusted one-year prevalence of migraine in females was significantly higher (p < 0.001) in students (41.9%) than in workers (19.2%) and blood donors (18.7%). Age-adjusted prevalence of migraine among males did not differ among the three groups: 4.5% in students, 4.9% in workers and 4.5% in blood donors. Age-adjusted prevalence of tension-type headache (TTH) among females was almost the same in students and blood donors (68.8% and 66.7%) but female workers had a lower prevalence of TTH (57%). Age-adjusted prevalence of TTH among males did not differ significantly between students and blood donors (55.8% and 58.1%) but male workers had a significantly lower (p < 0.001) prevalence of TTH (30.7%). The prevalence of chronic headache in students (TTH and/or migraine) was 3% and of probable medication-overuse headache 3%, significantly more than in workers and blood donors.
Conclusion
Headache prevalence was high and differed markedly among the three social groups. It is important that headache epidemiology also focus on socially defined groups in order to target future preventive efforts.
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Rapoport, A., Ravishankar, K., 2015-10-07 07:57:36 AM
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Petrusic, I., Podgorac, A., Zidverc-Trajkovic, J., Radojicic, A., Jovanovic, Z., Sternic, N., 2015-10-07 07:57:36 AM
Introduction
The aim of this study was to evaluate the prevalence and clinical impact of interictal microembolic signals (MES) in patients suffering from migraine with higher cortical dysfunction (HCD), such as language and memory impairment, during an aura.
Patients and methods
This study was carried out on 34 migraineurs with language and memory impairment during aura (HCD group), 31 migraineurs with only visual or visual and somatosensory symptoms during aura (Control group I), and 34 healthy controls (Control group II). We used a Doppler instrument to detect microemboli. Demographic data, disease features and the detection of MES between these groups, as well as the predictors of HCD during the aura, were analyzed.
Results
The duration of aura was longer and the frequency of aura was higher among patients with language and memory impairment during aura compared to Control group I. MES was detected in 29.4% patients from the HCD group, which was significantly higher compared to 3.2% in Control group I and 5.9% in Control group II. Regarding the absence or presence of MES, demographic and aura features were not different in the HCD subgroups. A longer duration of aura, the presence of somatosensory symptoms during the aura and the presence of interictal MES were independent predictors of HCD during the aura.
Conclusion
The present findings indicate that HCD and MES are related in patients with migraine with aura. Further research is needed to better understand the exact pathophysiological mechanism.
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Diener, H.-C., 2015-10-07 07:57:36 AM
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Gonzalez-Quintanilla, V., Toriello, M., Palacio, E., Gonzalez-Gay, M. A., Castillo, J., Montes, S., Martinez-Nieto, R., Fernandez, J., Rojo, A., Gutierrez, S., Pons, E., Oterino, A., 2015-10-07 07:57:36 AM
Background and objective
Unlike migraine and migraine with aura, little information exists regarding chronic migraine (CM) as a risk factor for cardiovascular disease. In this study we aim to determine whether an association between CM and endothelial dysfunction exists.
Methods
Individuals 18 years and older diagnosed with episodic migraine (EM) and CM according to ICHD criteria were studied. After an overnight fast and abstinence from vasoactive drugs, ultrasound studies were performed and blood samples taken from patients and matched controls according to internationally agreed on protocols.
Results
A total of 113 individuals were enrolled (35 CM, 37 EM, 41 controls). CM patients had a lower percentage of flow-mediated vasodilation (FMD; difference of means = 5.03%; p = 1.0E-6) and breath-holding index (BHI; difference of means 0.754; p = 2.0E-6), as well as increased carotid intima media thickness (cIMT; difference of means = 0.128 mm; p = 7.0E-5) than controls. The EM patients and controls comparison found similar, but less pronounced, differences: decreased BHI (p = 0.031), and increased cIMT (p = 0.028). Fibrinogen (r = 0.277; p = 0.006), C-reactive protein (r = 0.288; p = 0.003), and erythrocyte rate sedimentation (r = 0.298; p = 0.002) also correlated with cIMT, and inversely with BHImV and FMD.
Conclusions
Migraine is associated with systemic and cerebral endothelial dysfunction demonstrated by ultrasound studies and biological markers. The degree of these changes was strongly associated with the severity of migraine. Our data indicate that migraine may be a cerebral disorder with systemic endothelial damage.
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de Coo, I., Wilbrink, L., Haan, J., Ferrari, M., Terwindt, G., 2015-10-07 07:57:36 AM
Aim
In the revised criteria of the International Classification of Headache Disorders (ICHD-III beta) the following items are added to the diagnostic criteria of cluster headache: ipsilateral sensation of fullness in the ear and ipsilateral forehead/facial flushing. We evaluated the possible additional value of these symptoms for diagnosing cluster headache.
Methods
In this cross-sectional cohort study of (potential) cluster headache patients we investigated these additional symptoms using a Web-based questionnaire. Patients not fulfilling the ICHD-II criteria for cluster headache but fulfilling the ICHD-III beta criteria were interviewed.
Results
Response rate was 916/1138 (80.5%). Of all 573 patients with cluster headache according to ICHD-II criteria, 192 (33.5%) reported ipsilateral ear fullness and 113 (19.7%) facial flushing during attacks. There was no difference in reporting ipsilateral ear fullness and facial flushing between patients who received a diagnosis of cluster headache and patients who did not. None of the patients who did not fulfill all ICHD-II criteria could be categorized as cluster headache according to the ICHD-III beta criteria.
Conclusion
The results of this study do not support the addition of ear fullness and facial flushing to the new ICHD-III beta criteria.
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Gaul, C., Diener, H.-C., Silver, N., Magis, D., Reuter, U., Andersson, A., Liebler, E. J., Straube, A., on behalf of the PREVA Study Group, 2015-10-07 07:57:36 AM
Background
Chronic cluster headache (CH) is a debilitating disorder for which few well-controlled studies demon.strate effectiveness of available therapies. Non-invasive vagus nerve stimulation (nVNS) was examined as adjunctive prophylactic treatment of chronic CH.
Methods
PREVA was a prospective, open-label, randomised study that compared adjunctive prophylactic nVNS (n = 48) with standard of care (SoC) alone (control (n = 49)). A two-week baseline phase was followed by a four-week randomised phase (SoC plus nVNS vs control) and a four-week extension phase (SoC plus nVNS). The primary end point was the reduction in the mean number of CH attacks per week. Response rate, abortive medication use and safety/tolerability were also assessed.
Results
During the randomised phase, individuals in the intent-to-treat population treated with SoC plus nVNS (n = 45) had a significantly greater reduction in the number of attacks per week vs controls (n = 48) (–5.9 vs –2.1, respectively) for a mean therapeutic gain of 3.9 fewer attacks per week (95% CI: 0.5, 7.2; p = 0.02). Higher ≥50% response rates were also observed with SoC plus nVNS (40% (18/45)) vs controls (8.3% (4/48); p < 0.001). No serious treatment-related adverse events occurred.
Conclusion
Adjunctive prophylactic nVNS is a well-tolerated novel treatment for chronic CH, offering clinical benefits beyond those with SoC.
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Shin, R. K., Mejico, L. J., Boghen, D., 2015-10-07 07:57:36 AM
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Chong, C. D., Starling, A. J., Schwedt, T. J., 2015-10-07 07:57:36 AM
Background
Migraine attacks manifest with hypersensitivities to light, sound, touch and odor. Some people with migraine have photosensitivity between migraine attacks, suggesting persistent alterations in the integrity of brain regions that process light. Although functional neuroimaging studies have shown visual stimulus induced "hyperactivation" of visual cortex regions in migraineurs between attacks, whether photosensitivity is associated with alterations in brain structure is unknown.
Methods
Levels of photosensitivity were evaluated using the Photosensitivity Assessment Questionnaire in 48 interictal migraineurs and 48 healthy controls. Vertex-by-vertex measurements of cortical thickness were assessed in 28 people with episodic migraine who had interictal photosensitivity (mean age = 35.0 years, SD = 12.1) and 20 episodic migraine patients without symptoms of interictal photosensitivity (mean age = 36.0 years, SD = 11.4) using a general linear model design.
Results
Migraineurs have greater levels of interictal photosensitivity relative to healthy controls. Relative to migraineurs without interictal photosensitivity, migraineurs with interictal photosensitivity have thicker cortex in several brain areas including the right lingual, isthmus cingulate and pericalcarine regions, and the left precentral, postcentral and supramarginal regions.
Conclusion
Episodic migraineurs with interictal photosensitivity have greater cortical thickness in the right parietal-occipital and left fronto-parietal regions, suggesting that persistent light sensitivity is associated with underlying structural alterations.
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Raucci, U., Vanacore, N., Paolino, M. C., Silenzi, R., Mariani, R., Urbano, A., Reale, A., Villa, M. P., Parisi, P., 2015-10-07 07:57:36 AM
Background
Vertigo/Dizziness in childhood is not a rare cause of visits to the emergency department (ED). We analyzed a selected group with vertigo/dizziness to identify signs and symptoms that may help to guide the diagnostic approach and management.
Methods
A total of 616 children admitted for vertigo to the ED over a five-year period were retrospectively reviewed. Their medical history, clinical characteristics, laboratory and neuroimaging tests, final diagnoses and management were analyzed.
Results
Migraine and syncope were the most frequent causes. Two patients were affected by life-threatening cardiac syncope, while structural life-threatening central nervous system diseases were found in 15 patients, none of whom presented with vertigo as an isolated clinical finding.
Conclusions
Most cases of vertigo/dizziness in childhood that consist mainly of migraine and syncope are of benign origin. The prompt identification of neurological or cardiological signs or symptoms associated with vertigo in children is mandatory to rule out life-threatening conditions.
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Gil-Gouveia, R., Oliveira, A. G., Martins, I. P., 2015-10-07 07:57:36 AM
Background
The socio-economic impact of migraine is mostly related to work loss either by absenteeism or decreased work performance. Migraine-associated cognitive dysfunction during an attack may contribute to these difficulties.
Objective
The objective of this article is to analyze the presence and relevance of cognitive symptoms during migraine attacks and to relate their intensity and symptom-related disability with other migraine-defining symptoms.
Methods
Consecutive migraine patients of a headache clinic completed diaries scoring each migraine symptom (including cognitive symptoms) intensity and symptom-related disability.
Results
Of 100 consecutive patients included in this study, 34 (all females, age average 31.8 ± 8.8 years) returned information on 229 attacks, on average 6.7 per participant. Every symptom's intensity was always rated slightly higher than the disability it caused. Pain was the symptom scored with the highest intensity and disability, followed by cognitive symptoms (difficulty in thinking and worsening with mental effort) and photo- and phonophobia. Scoring was independent of any of the clinical variables. Attack intensity and disability scores correlated with intensity and disability from pain and from worsening with mental effort.
Conclusions
Attack-related cognitive symptoms are intense and disabling. Some attack-related cognitive symptoms correlate to intensity and disability subjectively attributed to the migraine attack. Cognitive performance should be addressed as a valuable secondary endpoint in trials of acute migraine treatment.
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Matosevic, B., Prieschl, M., Luef, G., Knoflach, M., Schmidauer, C., Willeit, J., Lackner, P., 2015-10-07 07:57:36 AM
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Schievink, W. I., Maya, M. M., 2015-10-07 07:57:36 AM
Background
Spontaneous intracranial hypotension due to a spinal cerebrospinal fluid (CSF) leak has become a well-recognized cause of headaches. Recently, various unusual neurological syndromes have been described in such patients with chronic ventral CSF leaks, including superficial siderosis and an amyotrophic lateral sclerosis-like syndrome. The authors now report two patients with spontaneous intracranial hypotension due to a chronic ventral CSF leak who suffered a diffuse non-aneurysmal subarachnoid hemorrhage (SAH).
Description of cases
A 62-year-old woman underwent uneventful microsurgical repair of a ventral thoracic CSF leak that had been present for 13 years. Seventeen months after surgery, she was found unresponsive and CT showed a diffuse intracranial SAH. Cerebral angiography and spine and brain MRI did not reveal a source of the SAH. A 73-year-old woman was found unresponsive and CT showed a diffuse intracranial SAH. Cerebral angiography and brain MRI did not reveal a source of the SAH, although superficial siderosis was detected. Spine MRI showed a ventral thoracic CSF leak that by history had been present for 41 years. She underwent uneventful microsurgical repair of the CSF leak.
Discussion
The authors suggest that patients with a ventral spinal CSF leak of long duration may be at risk of diffuse non-aneurysmal SAH.
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Tarasco, V., Grasso, G., Versace, A., Castagno, E., Ricceri, F., Urbino, A., Pagliero, R., 2015-10-07 07:57:36 AM
Aim
The aim of this article is to analyze the epidemiological and clinical features of migraine in a pediatric headache center.
Methods
A retrospective study was performed over six years. Hospital record databases were screened for the diagnosis of migraine with aura (MA) or without aura (MO), based on the ICHD-II criteria. Statistical analysis: Fisher's test or Mann-Whitney U test, significance at p < 0.05.
Results
Migraine was diagnosed in 495 children (29.7% MA, 70.3% MO). The majority of diagnoses were made between ages 9 and 14 years. After stratification for age into five groups, we observed an increase of diagnoses in females, with a peak after the age of 15 years, and an increase of MA. In both groups, the attacks were usually severe, infrequent (<1–3/month) lasting <2 hours, and associated with nausea/vomiting, photophobia, phonophobia (more frequent in MO). Osmophobia was reported in 24.7% of the patients with MO. Dizziness was more frequent in patients with MA. Visual auras were the most common occurrence (87.1%). Confusional state was observed in 10.88% of the patients. A positive family history of headache was observed in >88% of the patients.
Conclusion
We describe the characteristics of pediatric migraine based on the ICHD-II criteria, showing a likely significant loss of diagnoses using the ICHD-III beta. The incidence of migraine increases with age. MO occurs more commonly and shows more frequent attacks and a higher prevalence of associated symptoms, in particular osmophobia. Although males are prevalent in the entire sample, the proportion of females is higher among patients with MA in all of the age groups. Phenotype and sexual prevalence of migraine acquire adult characteristics and become more frequent in females from the onset of puberty.
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Ceylan, M., Bayraktutan, O. F., Becel, S., Atis, O., Yalcin, A., Kotan, D., 2015-10-07 07:57:36 AM
Background
Several studies have been conducted on the inflammatory aspects of migraine. Pentraxins are a novel and important part of innate immunity as a superfamily of acute phase proteins. In our study, we aimed to demonstrate the relationship between migraine and the serum levels of pentraxin-3 (PTX-3), C-reactive protein (CRP), fibrinogen and D-dimer.
Methods
We recruited 30 migraine patients (in both the attack and interictal period) and 30 healthy controls. Serum samples were obtained from all participants, and a brain MRI performed in the last six months was assessed regarding the presence of deep white matter lesions. Comparisons between the attack, interictal and control groups regarding the serum levels of PTX-3, CRP, fibrinogen and D-dimer were performed. The association between serum PTX-3 levels and migraine characteristics (disease duration, headache frequency, MRI findings, aura, family history, attack duration, and MIDAS score) was also assessed.
Results
We found higher serum levels of fibrinogen and PTX-3 in migraine attack patients compared with the interictal and control groups (p = 0.03 and p < 0.001, respectively). Subgroup analysis also showed that patients with a disease duration of more than five years and with an attack duration of more than 12 hours have lower serum levels of PTX-3 than patients who have a relatively new diagnosis and have relatively short-lasting migraine attacks (p = 0.042 and p = 0.038, respectively).
Conclusions
PTX-3 and fibrinogen exhibit different serum levels in patients undergoing a migraine attack compared with the interictal group and the controls. Participants with longer attacks and disease durations have lower serum levels of PTX-3, suggesting that inflammatory processes change along with disease progression.
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Bratbak, D. F., Nordgard, S., Stovner, L. J., Linde, M., Folvik, M., Bugten, V., Tronvik, E., 2015-10-07 07:57:36 AM
Objective
The main object of this pilot study was to investigate the safety of administering onabotulinumtoxinA (BTA) towards the sphenopalatine ganglion (SPG) in intractable chronic cluster headache. Efficacy data were also collected to provide indication on whether future placebo-controlled studies should be performed.
Method
In a prospective, open-label, uncontrolled study, we performed a single injection of 25 IU (n = 5) or 50 IU BTA (n= 5) towards the SPG in 10 patients with intractable chronic cluster headache with a follow-up of 24 weeks. The primary outcome was adverse events (AEs) and the main efficacy outcome was attack frequency in weeks 3 and 4 post-treatment.
Results
A total of 11 AEs were registered. There was one severe adverse event (SAE): posterior epistaxis. The number of cluster headache attacks (main efficacy outcome) was statistically significantly reduced in the intention-to-treat analysis from 18 ± 12 per week in baseline to 11 ± 14 (p = 0.038) in weeks 3 and 4, and five out of 10 patients had at least 50% reduction of attack frequency compared to baseline. The cluster attack frequency was significantly reduced for five out of six months post-treatment.
Conclusion
Randomised, placebo-controlled studies are warranted to establish the potential of this possible novel treatment of cluster headache.
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de Tommaso, M., Sciruicchio, V., Ricci, K., Montemurno, A., Gentile, F., Vecchio, E., Barbaro, M. G. F., Simeoni, M., Goffredo, M., Livrea, P., 2015-10-07 07:57:36 AM
Objectives
Few studies have addressed central sensitization symptoms and pain processing in childhood migraine. Our aims were to examine pain sensitivity and responses, including habituation, evoked by CO2 laser stimuli (laser-evoked potentials (LEPs)) in a cohort of children with migraine compared to non-migraine controls and to determine the correlation between LEP features and signs of central sensitization.
Methods
Thirty-five patients 8–15 years of age with migraines without aura were evaluated during the inter-critical phase and were compared to 17 controls. LEPs were analyzed, and their main features were correlated with clinical symptoms including allodynia and pericranial tenderness.
Results
The laser-evoked pain threshold was lower and the N2P2 vertex complex amplitude was higher in children with migraines. Furthermore, habituation of vertex waves of LEPs clearly showed a tendency toward progressive amplitude enhancement in the migraine group. Acute allodynia and inter-critical pericranial tenderness correlated with trigeminal LEP features, particularly with the abnormal habituation pattern.
Discussion
Abnormalities of pain processing and symptoms of central sensitization appear to be characteristics of children with migraine. Reduced habituation and progressive amplification of cortical responses to laser stimuli indicate an overactive nociceptive system at the onset of migraine, and this hyperactivity may subtend allodynia and pericranial tenderness. Future prospective trials may aid in the early identification of clinical phenotypes that display a tendency to develop into the chronic form of migraine, warranting a timely therapeutic approach.
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Luedtke, K., Allers, A., Schulte, L. H., May, A., 2015-10-07 07:57:36 AM
Aim
We aimed to conduct a systematic review evaluating the effectiveness of interventions used by physiotherapists on the intensity, frequency and duration of migraine, tension-type (TTH) and cervicogenic headache (CGH).
Methods
We performed a systematic search of electronic databases and a hand search for controlled trials. A risk of bias analysis was conducted using the Cochrane risk of bias tool (RoB). Meta-analyses present the combined mean effects; sensitivity analyses evaluate the influence of methodological quality.
Results
Of 77 eligible trials, 26 were included in the RoB assessment. Twenty trials were included in meta-analyses. Nineteen out of 26 trials had a high RoB in >1 domain. Meta-analyses of all trials indicated a reduction of TTH (p< 0.0001; mean reduction –1.11 on a 0–10 visual analog scale (VAS); 95% CI –1.64 to –0.57) and CGH (p = 0.0002; mean reduction –2.52 on a 0–10 VAS; 95% CI –3.86 to –1.19) pain intensity, CGH frequency (p < 0.00001; mean reduction –1.34 days per month; 95% CI –1.40 to –1.28), and migraine (p = 0.0001; mean reduction –22.39 hours without relief; 95% CI –33.90 to –10.88) and CGH (p < 0.00001; mean reduction –1.68 hours per day; 95% CI –2.09 to –1.26) duration. Excluding high RoB trials increased the effect sizes and reached additional statistical significance for migraine pain intensity (p < 0.00001; mean reduction –1.94 on a 0–10 VAS; 95% CI –2.61 to –1.27) and frequency (p < 0.00001; mean reduction –9.07 days per month; 95% CI –9.52 to –8.62).
Discussion
Results suggest a statistically significant reduction in the intensity, frequency and duration of migraine, TTH and CGH. Pain reduction and reduction in CGH frequency do not reach clinically relevant effect sizes. Small sample sizes, inadequate use of headache classification, and other methodological shortcomings reduce the confidence in these results. Methodologically sound, randomized controlled trials with adequate sample sizes are required to provide information on whether and which physiotherapy approach is effective. According to Grading of Recommendations Assessment, Development and Evaluation (GRADE), the current level of evidence is low.
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Cho, S.-J., Kim, B.-K., Kim, B.-S., Kim, J.-M., Kim, S.-K., Moon, H.-S., Song, T.-J., Cha, M.-J., Park, K.-Y., Sohn, J.-H., 2015-10-07 07:57:36 AM
Background
Vestibular migraine (VM), the common term for recurrent vestibular symptoms with migraine features, has been recognized in the appendix criteria of the third beta edition of the International Classification of Headache Disorders (ICHD-3β). We applied the criteria for VM in a prospective, multicenter headache registry study.
Methods
Nine neurologists enrolled consecutive patients visiting outpatient clinics for headache. The presenting headache disorder and additional VM diagnoses were classified according to the ICHD-3β. The rates of patients diagnosed with VM and probable VM using consensus criteria were assessed.
Results
A total of 1414 patients were enrolled. Of 631 migraineurs, 65 were classified with VM (10.3%) and 16 with probable VM (2.5%). Accompanying migraine subtypes in VM were migraine without aura (66.2%), chronic migraine (29.2%), and migraine with aura (4.6%). Probable migraine (75%) was common in those with probable VM. The most common vestibular symptom was head motion-induced dizziness with nausea in VM and spontaneous vertigo in probable VM. The clinical characteristics of VM did not differ from those of migraine without VM.
Conclusion
We diagnosed VM in 10.3% of first-visit migraineurs in neurology clinics using the ICHD-3β. Applying the diagnosis of probable VM can increase the identification of VM.
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Lane, R., Davies, P., 2015-10-07 07:57:36 AM
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Klein, J., Sandi-Gahun, S., Schackert, G., Juratli, T. A., 2015-10-07 07:57:36 AM
Objective
Peripheral nerve field stimulation (PNFS) is a promising modality for treatment of intractable facial pain. However, evidence is sparse. We are therefore presenting our experience with this technique in a small patient cohort.
Methods
Records of 10 patients (five men, five women) with intractable facial pain who underwent implantation of one or several subcutaneous electrodes for trigeminal nerve field stimulation were retrospectively analyzed. Patients' data, including pain location, etiology, duration, previous treatments, long-term effects and complications, were evaluated.
Results
Four patients suffered from recurrent classical trigeminal neuralgia, one had classical trigeminal neuralgia and was medically unfit for microvascular decompression. Two patients suffered from trigeminal neuropathy attributed to multiple sclerosis, one from post-herpetic neuropathy, one from trigeminal neuropathy following radiation therapy and one from persistent idiopathic facial pain. Average patient age was 74.2 years (range 57–87), and average symptom duration was 10.6 years (range 2–17). Eight patients proceeded to implantation after successful trial. Average follow-up after implantation was 11.3 months (range 5–28). Using the visual analog scale, average pain intensity was 9.3 (range 7–10) preoperatively and 0.75 (range 0–3) postoperatively. Six patients reported absence of pain with stimulation; two had only slight constant pain without attacks.
Conclusion
PNFS may be an effective treatment for refractory facial pain and yields high patient satisfaction.
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Schulte, L., May, A., 2015-10-07 07:57:36 AM
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Hagen, K., Wisloff, U., Ellingsen, O., Stovner, L. J., Linde, M., 2015-10-07 07:57:36 AM
Background
Evidence on the association between headache and physical fitness is conflicting. The aim of this population-based study was to examine the relationship between peak oxygen uptake (VO2peak) and headache, including migraine and tension-type headache (TTH).
Methods
In the third Nord-Trøndelag Health study (HUNT3), VO2peak was measured by ergospirometry in a sample of 4631 healthy adult participants. Of these, 3899 (54% women) also answered headache questions. The cross-sectional association between headache and VO2peak was evaluated by logistic regression using a categorical approach based on quintiles. Scores in the upper quintile were used as reference.
Results
Participants age 20–50 years had significant trends of increasing prevalence of any headache (p < 0.001), migraine (p < 0.001), TTH (p = 0.002) and unclassified headache (p = 0.027) with lower VO2peak. The highest prevalence odds ratios (ORs) were found in those with VO2peak in the lower quintile: For any headache the OR was 2.3 (95% confidence interval (1.6–3.3), for TTH 1.8 (1.2–2.8), for unclassified headache 1.9 (1.1–3.8), and for migraine 3.7 (2.1–6.6). Similar results were also found among those who reported physical activity levels in accordance with current recommendations of the American College of Sports Medicine but nevertheless had low VO2peak. Being in the lowest VO2peak quintile was also strongly associated with migraine aggravated by physical activity (OR 4.1, 2.1–8.1). No significant association was found between VO2peak and headache for those 50 years or older.
Conclusions
In this large cross-sectional study, an inverse relationship was found between VO2peak and headache for adults younger than 50 years of age.
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Chen, P.-K., Fuh, J.-L., Wang, S.-J., 2015-10-07 07:57:36 AM
Objective
Migraine is comorbid with restless legs syndrome (RLS). However, the temporal association between these two episodic disorders remains elusive. The current study investigated the temporal relationship between migraine and RLS attacks.
Methods
Migraine patients with RLS were recruited from a headache clinic. Patients with symptomatic RLS, RLS mimics, daily headaches, or daily RLS attacks were excluded. The patients recorded their headaches and RLS attacks for two weeks in a diary. The severity of each headache or RLS attack was rated on a four-point (0–3) Likert scale. Logit-normal, random-effects models were employed to estimate the odds ratios (ORs) for the temporal association between migraine and RLS attacks.
Results
Thirty migraine patients with RLS (28 F/2 M, mean age 35.5 ± 9.0 years) completed the study. On the basis of 420 daily diary records, migraine attacks were associated with subsequent RLS attacks occurring on the same and next nights (OR = 6.94, 95% confidence interval (CI) = 4.39–11.0 and OR = 3.00, CI = 1.92–4.68; both p < 0.001). RLS attacks were associated with subsequent migraine attacks only on Day 1 (OR = 1.97 (CI = 1.3–2.98;p = 0.01). Overall, the frequencies of migraine and RLS attacks in two weeks were correlated (Spearman's correlation = 0.56, p = 0.001).
Conclusions
Our study results showed a bidirectional triggering association between migraine and RLS attacks. The association was stronger and lasted longer for migraine triggering subsequent RLS than that for vice versa.
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Seo, J.-G., Park, S.-P., 2015-10-07 07:57:36 AM
Background
Almost one-third of patients with migraine do not adequately respond to triptans. We examined factors contributing to frovatriptan response in patients with migraine.
Methods
We enrolled new patients with migraine who consecutively visited our headache clinic. Eligible patients were instructed to take 2.5 mg of frovatriptan as soon as possible after migraine attack. The responsiveness was determined by whether headache was relieved or absent within 4 hours after the intake of frovatriptan. We assessed frovatriptan to be efficacious when headache responded to its administration in at least one of two successive migraine attacks and inefficacious when headache was not relieved in either attack. We included demographic, clinical and psychiatric variables in the analysis of factors associated with frovatriptan response.
Results
Of 128 eligible patients, 28 (21.9%) experienced frovatriptan inefficacy. In 24 patients with current major depressive disorder, 12 (50.0%) had frovatriptan inefficacy. Only current major depressive disorder was identified as a risk factor for inefficacy (odds ratio = 5.500, 95% confidence interval 2.103–14.382, p = 0.001).
Conclusions
Depression may be a risk factor of frovatriptan inefficacy in patients with migraine, even though half of patients with major depressive disorder respond to frovatriptan.
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Olesen, J., 2015-10-07 07:57:36 AM
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Viana, M., Linde, M., Sances, G., Ghiotto, N., Guaschino, E., Allena, M., Terrazzino, S., Nappi, G., Goadsby, P. J., Tassorelli, C., 2015-10-07 07:57:36 AM
Background
As there are no biological markers, a detailed description of symptoms, particularly temporal characteristics, is crucial when diagnosing migraine aura. Hitherto these temporal aspects have not been studied in detail.
Methods
We conducted a prospective diary-aided study of the duration and the succession of aura symptoms and their temporal relationship with headache.
Results
Fifty-four patients completed the study recording in a diary the characteristics of three consecutive auras (n = 162 auras). The median duration of visual, sensory and dysphasic symptoms were 30, 20 and 20 minutes, respectively. Visual symptoms lasted for more than one hour in 14% of auras (n = 158), sensory symptoms in 21% of auras (n = 52), and dysphasic symptoms in 17% of auras (n = 18). Twenty-six percent of patients had at least one aura out of three with one symptom lasting for more than one hour. In aura with multiple symptoms the subsequent symptom, second versus first one or third versus second, might either start simultaneously (34 and 18%), during (37 and 55%), with the end (5 and 9%), or after (24 and 18%) the previous aura symptom. The headache phase started before the aura (9%), simultaneously with the onset of aura (14%), during the aura (26%), simultaneously with the end of aura (15%) or after the end of aura (36%).
Conclusion
We provide data to suggest that symptoms may last longer than one hour in a relevant proportion of auras or migraine with aura patients, and that there is a high variability of scenarios in terms of time relationship among aura symptoms and between aura and headache.
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Minen, M. T., Loder, E., Tishler, L., Silbersweig, D., 2015-10-07 07:57:36 AM
Background
Studies reveal that migraine is often under-recognized, misdiagnosed and inadequately treated in the primary care setting.
Objective
The objective of this article is to assess primary care providers' (PCP) knowledge and needs regarding migraine diagnosis and management.
Methods
We held semi-structured group interviews and distributed a brief questionnaire to PCPs in our hospital network. Building on the information from the interviews, we developed a comprehensive survey assessing PCPs' knowledge about migraine. Descriptive analyses were performed.
Results
The initial interviews and brief questionnaires revealed that PCPs are aware of the prevalence of migraine but are uncertain about the details of management. Eighty-three of 120 physicians completed the comprehensive survey. Only 47% would order imaging for a new type of headache, 31% for worsening headache, and 35% for a headache unresponsive to treatment. Only 28% were familiar with the American Academy of Neurology guidelines on preventive treatment and 40% were familiar with the Choosing Wisely Campaign recommendations on migraine treatment. Just 34% were aware that opioids can cause medication-overuse headache. Non-pharmacologic treatment was not usually recommended. PCPs favored educational opportunities involving direct contact with headache physicians (56%).
Conclusions
PCPs are not universally aware of the specific recommendations for managing migraine patients. Future work should focus on innovative ways to provide decision support and education for PCPs caring for migraineurs.
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Chiang, C.-C., Schwedt, T. J., Wang, S.-J., Dodick, D. W., 2015-10-07 07:57:36 AM
Introduction
The objective of this review is to provide an evidence-based discussion of different treatment strategies for medication-overuse headache (MOH).
Method
We searched PubMed for articles discussing the treatment and prognosis of MOH published between 2004 and August 2014. Titles, abstract and articles were reviewed systematically. The level of evidence provided by each study of the included articles was determined according to the American Academy of Neurology Clinical practice guideline manual. We discuss the level of evidence to support the early discontinuation/withdrawal of overused medications, the level of evidence to support the use of preventive treatment, the short- and long-term prognosis, and the outcome according to the class of drug overused in patients diagnosed with MOH.
Results
The initial search resulted in 1313 articles; 68 articles met our inclusion criteria and were discussed. The level of evidence to support early discontinuation of overused medications alone is low due to the absence of controlled studies. Adding preventive medication to early discontinuation led to a better outcome than early discontinuation alone. For patients with chronic migraine (CM) and medication overuse (MO), there are large randomized control trials supporting the use of onabotulinumtoxinA and topiramate without early discontinuation of overuse; however, the evidence is limited since data were obtained from post hoc analysis.
Conclusion
Considering current available evidence and the systemic toxicity of overusing acute headache medication, we suggest discontinuation of the overused medication with the addition of preventive medication. Appropriately sized, randomized controlled trials evaluating the safety and long-term efficacy of preventive medication plus early discontinuation of overuse vs preventive medication alone vs early discontinuation of overuse alone are needed.
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Asberg, A. N., Stovner, L. J., Zwart, J.-A., Winsvold, B. S., Heuch, I., Hagen, K., 2015-10-07 07:57:36 AM
Background
There is conflicting evidence for the association between migraine and increased mortality risk. The aim of this study was to investigate the relationship between migraine and non-migrainous headache, and all-cause mortality and cardiovascular mortality.
Methods
In this prospective population-based cohort study from Norway, we used baseline data from the second Nord-Trøndelag Health Survey (HUNT2), performed between 1995 and 1997 in the County of Nord-Trøndelag. These data were linked with a comprehensive mortality database with follow-up through the year 2011. A total of 51,853 (56% of invited) people were categorized based on their answers to the headache questions in HUNT2 (headache free, migraine or non-migrainous headache). Hazard ratios (HRs) of mortality during a mean of 14.1 years of follow-up were estimated using Cox regression.
Results
During the follow-up period 9408 died, 4321 of these from cardiovascular causes. There was no difference in all-cause mortality between individuals with migraine and non-migrainous headache compared to those without headache or between headache status and mortality by cardiovascular disease. There was, however, among men with migraine without aura a reduced risk of death by cardiovascular diseases (HR 0.72, 95% confidence interval 0.56–0.93). This relationship was not evident in women.
Conclusion
In this large, prospective cohort study there was no evidence for a higher all-cause mortality or cardiovascular mortality among individuals with migraine.
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Riesco, N., Perez-Alvarez, A. I., Verano, L., Garcia-Cabo, C., Martinez-Ramos, J., Sanchez-Lozano, P., Cernuda-Morollon, E., Pascual, J., 2015-10-07 07:57:36 AM
Background
Cranial autonomic symptoms (CAS) seem to appear in around half of migraine patients.
Objective
Our aim was to analyse the prevalence and profile of CAS, mainly of cranial autonomic parasympathetic symptoms (CAPS), in a series of patients with chronic migraine (CM) according the new criteria for autonomic symptoms in the current IHS classification.
Patients and methods
We recruited consecutive CM patients attending our headache clinic. Five CPAS were surveyed: lacrimation, conjunctival injection, eyelid oedema, ear fullness and nasal congestion. They were graded as 0 (absent), 1 (present and mild) and 2 (present and conspicuous); therefore the score in this CAPS scale ranges from 0 to 10 points. As a cranial autonomic sympathetic symptom (CSAS), we also asked about the presence of ptosis.
Results
We interviewed 100 CM patients. Their mean age was 45 years (18–63 years); 93 were females. Eighteen had no CAPS, while 82 reported at least one CAPS. There were only six patients with scores higher than 5, the mean and median CAPS being 2.1 and 2, respectively. Prevalence of CAPS was lacrimation (49%), conjunctival injection (44%), eyelid oedema (39%), ear fullness (30%) and nasal congestion (20%). Ptosis was reported by 42.
Conclusion
These results, by using for the first time an easy quantitative scale, confirm that (mild) CAPS are not the exception but the rule in CM patients. The score in this CAPS scale could be of help as a further endpoint in clinical trials or to be correlated with potential biomarkers of parasympathetic activation in primary headaches.
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Krogh, A.-B., Larsson, B., Salvesen, O., Linde, M., 2015-10-07 07:57:36 AM
Aim
The aim of this article was to develop and apply an Internet-based headache diary (i-diary) for adolescents and compare it with a paper-diary (p-diary) regarding adherence, user acceptability and recorded headache activity.
Methods
In a cross-sectional school-based study, a representative sample of 488 adolescents aged 12–18 years were randomly allocated by cluster sampling to record for three weeks in i-diaries or p-diaries their headache intensity, disability, and use of acute medication.
Results
A significantly (p = 0.008) higher proportion of adolescents in the i-diary group used the diary at least once during the 21-day period (86% vs 76% for the p-diary). However, the p-diary group completed a significantly (p< 0.001) higher number of diary days (20.8 vs 15.0 days for the i-diary). The response rate for the i-diary-group was largely evenly distributed over the study period; conversely, approximately two-thirds of the adolescents using the p-diary responded on all 21 days, whereas one-fourth did not respond at all. The two diary types were rated as equal in easiness to remember (p = 0.25), but the i-diaries were more bothersome to use (p = 0.029).
Conclusion
Although p-diary users completed a higher proportion of diary days, i-diaries provided more reliable and credible estimates of headache parameters because of better real-time assessment.
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John, S., Singhal, A. B., Calabrese, L., Uchino, K., Hammad, T., Tepper, S., Stillman, M., Mills, B., Thankachan, T., Hajj-Ali, R. A., 2015-10-07 07:57:36 AM
Background
Long-term outcomes of reversible cerebral vasoconstriction syndrome (RCVS) have not been systematically investigated.
Methods
The following validated questionnaires were mailed to patients recruited from the RCVS registries of two academic hospitals: headache screening form, Headache Impact Test, Migraine Disability Assessment Test, Barthel Index (BI), EuroQoL (EQ-5D-5L) and Patient Health Questionnaire (PHQ-9).
Results
Of the 191 patients in the registries, 109 could be contacted and 45 responded. Median follow-up time after symptom onset was 78 months. After RCVS resolution, 24 (53%) patients continued to have headache, but the majority (88%) reported improvement in its severity. Thirteen of the 24 patients with persistent headache had a history of migraine prior to RCVS diagnosis. The majority (97.5%) of respondents were functionally independent based on BI scores. EQ-5D-5L showed better scores in the domains of mobility, self-care and usual activities, as compared to pain and anxiety/depression. Patients with persistent headache had significantly higher levels of EQ-5D-5L pain scores. PHQ-9 scores revealed only one patient (3%) with severe depression.
Conclusion
More than half of RCVS patients will continue to have chronic headaches of mild to moderate intensity that are distinct from the "thunderclap" headaches at RCVS onset. The vast majority regain complete functional ability. However, pain and anxiety/depression are frequent, often aggravated by concomitant chronic headaches, and may be associated with lower quality of life.
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Sabre, L., Rugo, M., Asser, T., Korv, J., Braschinsky, M., 2015-10-07 07:57:36 AM
Background
Patients with traumatic spinal cord injury (TSCI) often suffer from different types of pain. However, headaches after TSCI have not been studied.
Aim
The aim of this article is to examine the occurrence of headache among patients with TSCI.
Methods
This cross-sectional study included individuals with TSCI from 1997 to 2012 in Estonia. Patients with TSCI were interviewed via telephone. The interview was based on a questionnaire specifically designed to identify headache type using the International Classification of Headache Disorders, third edition (beta version).
Results
There were 73 patients with a mean age 37.1 ± 10.6 years. The mean time since TSCI was 7.5 ± 4.0 years. The most frequently mentioned pain was headache (71%), followed by back pain (60%) and pain in neck (44%).
Headaches were more frequent after the trauma compared with the headaches before TSCI (71% vs 51%, p = 0.02). Headaches that arose after TSCI were not related to the concomitant brain injury (p = 0.15). The occurrence of headache did not depend on the severity or the level of the TSCI.
Eighty-five percent of patients had not contacted any physician and headache was not diagnosed.
Conclusions
This is the first study that evidentially shows that headache is the most prevalent pain condition after TSCI. Despite this, the majority of patients never consult a physician, nor is their headache diagnosed or appropriately managed. This indicates that further studies are needed to provide evidence regarding the prevalence and causes of headache and its impact on quality of life.
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Orr, S. L., 2015-10-07 07:57:36 AM
Background
The use of complementary and alternative medicines (CAM) is common among patients with primary headaches. In parallel, CAM research is growing. Diet interventions comprise another category of non-pharmacologic treatment for primary headache that is of increasing clinical and research interest.
Methods
A literature search was carried out to identify studies on the efficacy of diet and nutraceutical interviews for primary headache in the pediatric and adult populations. MEDLINE, Embase and EBM Reviews—Cochrane Central Register of Controlled Trials were searched to identify studies.
Results
There is a growing body of literature on the potential use of CAM and diet interventions for primary headache disorders. This review identified literature on the use of a variety of diet and nutraceutical interventions for headache. Most of the studies assessed the efficacy of these interventions for migraine, though some explored their role in tension-type headache and cluster headache. The quality of the evidence in this area is generally poor.
Conclusions
CAM is becoming more commonplace in the headache world. Several interventions show promise, but caution needs to be exercised in using these agents given limited safety and efficacy data. In addition, interest in exploring diet interventions in the treatment of primary headaches is emerging. Further research into the efficacy of nutraceutical and diet interventions is warranted.
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Pressman, A., Jacobson, A., Eguilos, R., Gelfand, A., Huynh, C., Hamilton, L., Avins, A., Bakshi, N., Merikangas, K., 2015-10-07 07:57:36 AM
Introduction
The growing availability of electronic health data provides an opportunity to ascertain diagnosis-specific cases via systematic methods for sample recruitment for clinical research and health services evaluation. We developed and implemented a migraine probability algorithm (MPA) to identify migraine from electronic health records (EHR) in an integrated health plan.
Methods
We identified all migraine outpatient diagnoses and all migraine-specific prescriptions for a five-year period (April 2008–March 2013) from the Kaiser Permanente, Northern California (KPNC) EHR. We developed and evaluated the MPA in two independent samples, and derived prevalence estimates of medically-ascertained migraine in KPNC by age, sex, and race.
Results
The period prevalence of medically-ascertained migraine among KPNC adults during April 2008–March 2013 was 10.3% (women: 15.5%, men: 4.5%). Estimates peaked with age in women but remained flat for men. Prevalence among Asians was half that of whites.
Conclusions
We demonstrate the feasibility of an EHR-based algorithm to identify cases of diagnosed migraine and determine that prevalence patterns by our methods yield results comparable to aggregate estimates of treated migraine based on direct interviews in population-based samples. This inexpensive, easily applied EHR-based algorithm provides a new opportunity for monitoring changes in migraine prevalence and identifying potential participants for research studies.
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Foote, H. W., Hamer, J. D., Roland, M. M., Landy, S. R., Smitherman, T. A., 2015-10-07 07:57:36 AM
Background
Studies of musculoskeletal pain patients confirm that acceptance of pain and values-based action are strong predictors of pain-related disability and that interventions fostering "psychological flexibility" confer positive outcomes. However, data on these processes in migraine remain limited. This cross-sectional study examined relations between components of psychological flexibility and headache among treatment-seeking migraineurs.
Methods
A total of 103 adults (M age = 41.5 (11.9) years; 88.2% female) with ICHD-confirmed migraine (71.8% episodic, 28.2% chronic) across three clinics completed measures of psychological flexibility and headache-related disability. Hierarchical regressions quantified relations between acceptance/values-based action and headache variables after first controlling for pain severity and gender.
Results
Acceptance of pain and values-based action accounted for 10% of unique variance in headache severity (R2 p = 0.006) and up to 20% in headache-related disability (R2 ps = 0.02 and < 0.001) but were weakly related to headache frequency. Psychological flexibility was more strongly associated with MIDAS-measured disability than was headache severity or headache frequency. Significant effects were typically of medium-to-large size and driven primarily by values-based action.
Conclusions
Paralleling results from the broader chronic pain literature, pain acceptance and values-based action play significant roles in headache pain and disability. Further study of interventions targeting these processes may enhance existing treatments.
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Ambrosini, A., Iezzi, E., Perrotta, A., Kisialiou, A., Nardella, A., Berardelli, A., Pierelli, F., Schoenen, J., 2015-10-07 07:57:36 AM
Introduction
In migraine most studies report an interictal deficit of habituation of visual-evoked potentials (VEP-hab) and reduced thresholds for phosphene induction (PT) by transcranial magnetic stimulation (TMS). We searched for a possible correlation between VEP-hab and PT in migraine patients and healthy controls to test whether they reflect the same pathophysiological abnormality.
Methods
We assessed PT and VEP-hab measured as the percentage change of N1/P1 amplitude over six blocks of 100 responses in 15 healthy volunteers (HV) and in 13 episodic migraineurs without aura (MO) between attacks. Results were compared using Mann-Whitney U test. Interrelationships were examined using Spearman's correlation.
Results
In MO patients VEP-hab was reduced compared to HV (p = 0.001), while PT were not significantly different between HV and MO. There was no correlation between PT and VEP-hab in either group of participants.
Conclusions
We confirm that in interictal migraine VEP habituation is deficient, but magnetophosphene threshold normal. VEP-hab and PT were not correlated with each other in healthy controls or in migraineurs. This finding suggests that they index different facets of cortical excitability in migraine, i.e. a punctual normal measure of the cortical activation threshold for PT and a dynamic response pattern to repeated stimuli for VEP habituation.
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Heyer, G. L., Young, J. A., Rose, S. C., McNally, K. A., Fischer, A. N., 2015-10-07 07:57:36 AM
Objective
The term "post-traumatic migraine" (PTM) has been used to describe post-traumatic headaches (PTHs) that have associated migraine features, but studies of this relationship are lacking. The objective of the present study was to determine whether PTH correlates strongly with migraine symptoms among youth with concussion.
Methods
Twenty-three symptoms were analyzed from a retrospective cohort of 1953 pediatric patients with concussion. A principal component analysis (PCA) with oblique Promax rotation was conducted to explore underlying symptom relationships in the full cohort and in subcohorts stratified by the presence (n = 414) or absence (n = 1526) of premorbid headache.
Results
The mean patient age was 14.1 years; 63% were male. Headache was the most common postconcussion symptom, acknowledged by 69.4% of patients. When considering the full cohort, the PCA demonstrated clustering of headache with photophobia, phonophobia, nausea, dizziness, and neck pain. Similar clustering was present among patients without premorbid headaches. Repeating the analysis in the patients with preconcussion headaches led to elimination of neck pain from the cluster.
Conclusions
PTH correlates strongly with other migraine symptoms among youth with concussion, regardless of premorbid headaches. This clustering of migraine symptoms supports the existence of PTM as a distinct clinical entity in some patients.
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Husoy, A. K., Indergaard, M. K., Honningsvag, L.-M., Haberg, A. K., Hagen, K., Linde, M., Garseth, M., Stovner, L. J., 2015-10-07 07:57:36 AM
Background
In four previous clinic-based MRI studies headache sufferers (in particular migraineurs) had more perivascular spaces (PVS) than individuals who were headache-free.
Methods
The present study was part of a large longitudinal, epidemiological study (Nord-Trøndelag Health Survey (HUNT)). The 1006 participants, age 50–65 years at inclusion, had participated in all previous HUNT surveys (1–3), and been randomly selected to a population-based imaging study of the head (HUNT-MRI, 2007–2009). The number of visible PVS in the basal ganglia (BG) and hemispheric white matter (HWM) was compared in headache sufferers (migraine with and without aura, non-migrainous headache) and people who were headache-free.
Results
The results showed in general small differences between headache sufferers and headache-free participants. In the cross-sectional analysis migraineurs without aura had fewer PVS than headache-free individuals in BG (OR = 0.84, 95% CI = 0.76--0.94, p value = 0.003) and in BG and HWM together (OR = 0.97, 95% CI = 0.95-1.00, pvalue = 0.046). No difference between long-term headache sufferers and long-term headache-free individuals with regard to number of PVS was found.
Discussion
In contrast to previous studies, the present large, blinded, population-based study showed no increase in number of dilated PVS among headache sufferers. Fewer PVS among those with migraine without aura may be a spurious finding.
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Kobayashi, M., 2015-10-07 07:57:36 AM
Background
Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by recurrent thunderclap headaches with reversible cerebral vasoconstriction, and often precipitated by the postpartum state and vasoactive medications. We describe a case of a patient with RCVS induced by amezinium metilsulfate, a sympathomimetic drug, in whom magnetic resonance angiography (MRA) initially revealed diffusely dilated cerebral arteries.
Case description
A 34-year-old woman was prescribed amezinium metilsulfate for hypotension. Twelve days later, she suffered from abrupt severe headaches and was referred to our department. She had no neurological deficits; however, MRA revealed diffusely dilated anterior, middle, and posterior cerebral arteries with vasoconstriction. She was tentatively diagnosed with RCVS and successfully treated with verapamil for headache. Nevertheless, follow-up MRAs disclosed widespread segmental vasoconstriction that resolved in two months.
Discussion
Diffuse cerebrovascular dilation has not been addressed but may be associated with RCVS pathophysiology. In addition, physicians should bear in mind that amezinium metilsulfate can potentially induce RCVS.
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Bilgic, B., Kocaman, G., Arslan, A. B., Noyan, H., Sherifov, R., Alkan, A., Asil, T., Parman, Y., Baykan, B., 2015-10-07 07:57:36 AM
Background
Chronic migraine (CM) is a disabling neurologic condition that often evolves from episodic migraine. There has been mounting evidence on the volumetric changes detected by magnetic resonance imaging (MRI) technique in migraineurs. These studies mainly focused on episodic migraine patients and less is known about the differences in CM patients.
Method
A total of 24 CM patients and 24 healthy control individuals (all females) were included in this study. All participants underwent neurological examination and MRI. High-resolution anatomical MRI images were processed with an automated segmentation method (FreeSurfer). White-matter abnormalities of the brain were also evaluated with the Age-Related White-Matter-Changes Scale.
Results
The volumes of the cerebellum and brainstem were found to be smaller in CM patients compared to healthy controls. White-matter abnormalities were also found in CM patients, specifically in the bilateral parieto-occipital areas. There was no correlation between the clinical variables and volume decrease in these regions.
Conclusion
CM patients showed significant volume differences in infratentorial areas and white-matter abnormalities in the posterior part of the brain. It is currently unclear whether the structural brain changes seen in migraine patients are the cause or the result of headaches. Longitudinal volumetric neuroimaging studies with larger groups, especially on the chronification of migraine, are needed to shed light on this topic.
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Lipton, R. B., Serrano, D., Buse, D. C., Pavlovic, J. M., Blumenfeld, A. M., Dodick, D. W., Aurora, S. K., Becker, W. J., Diener, H.-C., Wang, S.-J., Vincent, M. B., Hindiyeh, N. A., Starling, A. J., Gillard, P. J., Varon, S. F., Reed, M. L., 2015-10-07 07:57:36 AM
Background
Migraine, particularly chronic migraine (CM), is underdiagnosed and undertreated worldwide. Our objective was to develop and validate a self-administered tool (ID-CM) to identify migraine and CM.
Methods
ID-CM was developed in four stages. (1) Expert clinicians suggested candidate items from existing instruments and experience (Delphi Panel method). (2) Candidate items were reviewed by people with CM during cognitive debriefing interviews. (3) Items were administered to a Web panel of people with severe headache to assess psychometric properties and refine ID-CM. (4) Classification accuracy was assessed using an ICHD-3β gold-standard clinician diagnosis.
Results
Stages 1 and 2 identified 20 items selected for psychometric validation in stage 3 (n = 1562). The 12 psychometrically robust items from stage 3 underwent validity testing in stage 4. A scoring algorithm applied to four symptom items (moderate/severe pain intensity, photophobia, phonophobia, nausea) accurately classified most migraine cases among 111 people (sensitivity = 83.5%, specificity = 88.5%). Augmenting this algorithm with eight items assessing headache frequency, disability, medication use, and planning disruption correctly classified most CM cases (sensitivity = 80.6%, specificity = 88.6%).
Discussion
ID-CM is a simple yet accurate tool that correctly classifies most individuals with migraine and CM. Further testing in other settings will also be valuable.
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Steppacher, I., Schindler, S., Kissler, J., 2015-10-07 07:57:36 AM
Background
Migraine is a disorder of periodic disabling headache. Facilitated cortical responsivity has been suggested as one predisposing factor. Although the underlying mechanisms of migraine attack onsets are not fully understood, facilitated cortical responsivity has been suggested as one predisposing factor. Here, we investigate if enhanced cortical responsivity is reflected in altered event-related potentials during processing of complex pictures.
Method
Altogether, 16 migraine patients and 16 healthy volunteers participated in this study. Each patient had a diagnosed migraine and was headache- and medication-free for the study. Participants watched positive, negative and neutral pictures from the international affective picture system. An electroencephalogram was recorded during picture presentation. Afterwards, participants were asked to rate the pictures for valence and arousal.
Results
Migraine patients showed significantly more negative-going early event-related potential components from 100 ms to 180 ms to all picture categories over occipital regions as well as more positive-going late potentials over central regions. Patients and controls did not differ in valence and arousal ratings for the international-affective picture system.
Discussion
Patients with migraine seem to react cortically more intensely to all kinds of pictorial stimuli, regardless of emotional content. This facilitated processing may be related to the high cortical responsivity shown in various other event-related potential studies and might contribute to the recurring intense headache attacks.
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Garcia-Moreno, H., Cuadrado, M.-L., 2015-10-07 07:57:36 AM
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Zhang, Y., Kong, Q., Chen, J., Li, L., Wang, D., Zhou, J., 2015-10-07 07:57:36 AM
Objectives
This study explored the clinical characteristics of vestibular migraine in Chinese subjects and performed a field test of the criteria of the International Classification of Headache Disorders 3rd edition beta version.
Methods
Consecutive patients with vestibular migraine were surveyed and registered in a headache clinic during the study period. The diagnosis of vestibular migraine was made according to International Classification of Headache Disorders 3rd edition beta version. Assessments included standardized neuro-otology bedside examination, pure-tone audiogram, bithermal caloric testing, neurological imaging, cervical X-ray or magnetic resonance imaging, Doppler ultrasound of cerebral arteries and laboratory tests.
Results
A total of 67 patients (62 female/five male, 47.8 ± 10.3 years old) were enrolled in this study. The mean ages of migraine and vertigo onset were 32.2 ± 11.5 and 37.9 ± 10.1 years, respectively. The most common migraine subtype was migraine without aura (79%), followed by migraine with aura (12%) and chronic migraine (9%). The duration of vertigo attacks varied from seconds to days and 25% of patients had attacks that lasted less than 5 minutes. Among the patients with short-lasting attacks, 75% of these patients had ≥5 attacks per day within 72 hours. Auditory symptoms were reported in 36% of the patients. Migraine prophylactic treatments were effective in 77% of the patients.
Conclusions
Our study showed that the clinical features of vestibular migraine in China were similar to those of Western studies. The definition of vertigo episodes and migraine subtypes of vestibular migraine in International Classification of Headache Disorders 3rd edition beta version might be modified further. More than five vertigo attacks per day within 72 hours might be helpful as far as identifying vestibular migraine patients with short-lasting attacks.
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Koenig, J., Williams, D. P., Kemp, A. H., Thayer, J. F., 2015-10-07 07:57:36 AM
Objective
Vagal nerve activity—indexed by heart rate variability (HRV)—has been linked to altered pain processing and inflammation, both of which may underpin headache disorders and lead to cardiovascular disease (CVD). Here we examined the evidence for differences in parasympathetic (vagal) activity indexed by time- and frequency-domain measures of HRV in patients with headache disorders compared to healthy controls (HCs).
Methods
A systematic review and meta-analysis was conducted on studies investigating group differences in vagally mediated HRV (vmHRV) including time- (root-mean-square of successive R-R-interval differences (RMSSD)) and frequency- (high-frequency HRV) domain measures. Studies eligible for inclusion were identified by a systematic search of the literature, based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.
Results
Seven studies reporting a total of 10 comparisons of patients with headache disorders (HF-HRV n = 67, RMSSD n= 122) and HCs (HF-HRV n = 64, RMSSD n = 125) were eligible for inclusion. Random-effects meta-analysis revealed a significant main effect on RMSSD (Z = 2.03, p = 0.04; Hedges' g = –0.63; 95% CI (–1.24, –0.02); k = 6) and similar pooled effect size estimates for HF-HRV when breathing was controlled (g = –0.30; 95% CI (–0.69; 0.10)) but not when breathing was not controlled (g = 0.02; 95% CI (–0.69; 0.74)). Controlling for breathing had no effect on RMSSD.
Conclusion
vmHRV is reduced in patients with headache disorders, findings associated with a medium effect size. Suggestions for future research in this area are provided, emphasizing a need to investigate the impact of headache disorders and commonly comorbid conditions—including mental disorders—as well as the investigation of the risk for CVD in migraine in particular. We further emphasize the need for large-scale studies to investigate HRV as a mechanism mediating the association of migraine and CVD.
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Postma, I., van Oosterhout, W., de Groot, J., Terwindt, G., Zeeman, G., 2015-10-07 07:57:36 AM
Introduction
Identifying female-specific risk markers for cerebrovascular disease is becoming increasingly important. Both migraine and preeclampsia have been associated with higher incidence of brain white matter lesions (WML) and stroke. We assessed the association between WML and migraine among formerly (pre)eclamptic women.
Methods
A total of 118 women (76 formerly (pre)eclamptic and 42 control women) were screened for migraine and WML presence. Independent effects of migraine and (pre)eclampsia on WML were assessed.
Results
Migraine prevalence did not differ between the (pre)eclamptic (26/76; 34%); and control group (10/42; 24%), p= 0.17. Age-adjusted regression analysis failed to show a significant independent effect of migraine (OR 1.14; 95% CI 0.47–2.76; p = 0.77) on WML presence, and showed a non-significant effect of (pre)eclampsia (OR 2.30; 95% CI 0.90–5.83; p = 0.08).
Conclusion
Migraine prevalence was not found to be an independent risk factor for WML prevalence in formerly (pre)eclamptic women. Since this study had a small sample size, larger prospective studies are needed to examine female-specific risk factors for WML and its consequences.
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Gungor, F., Akyol, K. C., Kesapli, M., Celik, A., Karaca, A., Bozdemir, M. N., Eken, C., 2015-10-07 07:57:36 AM
Objective
Migraine is a leading headache etiology that frequently presents to the emergency department (ED). In the present study, we aimed to determine the efficacy of dexketoprofen in aborting migraine headaches in the ED.
Methods
This prospective, randomized, double-blind study was conducted in an ED of a tertiary care hospital using allocation concealment. Patients were allocated into two arms to receive the study drug; 50 mg dexketoprofen in 50 ml saline and 50 ml saline as placebo. Change in pain intensity was measured by the visual analog scale at baseline, both at 30 and 45 minutes after the study medication was administered. Rescue medication requirement and pain relapse were also recorded by a telephone follow-up at 48 hours.
Results
A total of 224 patients (112 in each group) were included into the final analysis. Mean age of the study participants was 37 ± 11 (SD) and 25% (n = 56) of them were male. The median pain improvement at 45 minutes for patients receiving dexketoprofen was 55 (IQR: 49 to 60) and 30 (IQR: 25 to 35) for those receiving placebo. The mean difference between the two groups at 45 minutes was 21.4 (95% CI: 14.4. to 28.5). Rescue drugs were needed in 22.3% of patients who received dexketoprofen compared to 55.4% in patients who received placebo (dif: 33.1%; 95% CI: 20% to 45%). There were no adverse events reported in either group during the study period.
Conclusion
Intravenous dexketoprofen is superior to placebo in relieving migraine headaches in the ED. It may be a suitable therapy with minimum side effects in patients presenting with a migraine headache to the ED.
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Blicher, J. U., Tietze, A., Donahue, M. J., Smith, S. A., Ostergaard, L., 2015-10-07 07:57:36 AM
Introduction
To investigate tissue flow disturbance and hypoxia during migraine aura, we studied a case of familial hemiplegic migraine (FHM) using novel magnetic resonance imaging (MRI) techniques.
Case results
A 44-year-old male was admitted with suspected stroke because of confusion and aphasia. Initial gadolinium-based perfusion MRI showed a decrease in cerebral blood flow and an increase in capillary flow disturbances within the left hemisphere. Later during the prolonged aura phase, chemical exchange saturation transfer MRI indicated a drop in pH in the affected area. The patient was diagnosed with an R908Q mutation in the ATP1A2gene causing FHM type 2.
Discussion
During prolonged aura in FHM, MRI shows reduced CBF, capillary flow disturbances and a possible pH drop that could indicate tissue hypoxia.
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Yamada, K., 2015-10-07 07:57:36 AM
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Chen, Y.-C., Wang, Y.-F., Li, J.-Y., Chen, S.-P., Lirng, J.-F., Hseu, S.-S., Tung, H., Chen, P.-L., Wang, S.-J., Fuh, J.-L., 2015-10-07 07:57:36 AM
Objective
The objective of this article is to elucidate the outcome, prognostic predictors and timing of surgical intervention for subdural hematoma (SDH) in patients with spontaneous intracranial hypotension (SIH).
Methods
Patients with SDH were identified retrospectively from 227 consecutive SIH patients. Data were collected on demographics, clinical courses, neuroimaging findings, and treatment of SDH, which was later divided into conservative treatment, epidural blood patches (EBP), and surgical intervention. Poor outcome was defined as severe neurological sequelae or death.
Results
Forty-five patients (20%) with SDH (mean maximal thickness 11.9 ± 6.2 mm) were recruited. All 15 patients with SDH <10 mm achieved good outcomes by either conservative treatment or EBP. Of 30 patients with SDH ≥10 mm, patients with uncal herniation (n = 3) had poor outcomes, even after emergent surgical evacuation (n = 2), compared to those without (n = 27) (100% vs. 0%, p < 0.001). Fourteen patients underwent surgical evacuation, resulting in good outcomes in all 12 who received early intervention and poor outcomes in the remaining two who received delayed intervention after Glasgow Coma Scale (GCS) score ≤8 (100% vs. 0%, p = 0.01).
Conclusions
Uncal herniation results in poor outcomes in patients with SIH complicated with SDH. In individuals with SDH ≥10 mm and decreased GCS scores, early surgical evacuation might prevent uncal herniation.
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Hansen, J. M., Goadsby, P. J., Charles, A. C., 2015-10-07 07:57:36 AM
Background
There is significant variability in the clinical presentation of migraine, both among patients, and between attacks in an individual patient. We examined clinical features of migraine with aura in a large group of patients enrolled in a clinical trial, and compared retrospective migraine attack characteristics reported upon enrollment in the trial with those recorded prospectively in the trial.
Methods
Patients with migraine (n = 267) with typical visual aura in more than 30% of their attacks were enrolled from 16 centers for a clinical trial. Upon enrollment, patients provided a detailed retrospective description of the clinical features of their attacks of migraine. During the trial, clinical symptoms in migraine attacks starting with aura were recorded prospectively in 861 attacks.
Results
Retrospectively reported visual aura symptoms were variable and often overlapping; the most common symptoms were dots or flashing lights, wavy or jagged lines, blind spots, and tunnel vision. Multiple patients reported more than one visual phenomenon. Approximately half of the patients reported nonvisual aura symptoms, the most common were numbness and tingling, followed by difficulty in recalling or speaking words. A significant percentage of patients also reported a change in olfaction. There were several inconsistencies between the features of prospectively recorded and retrospectively reported attacks. Headache, nausea, photophobia, and phonophobia were all less common in prospectively recorded attacks as compared with retrospective reporting. Nausea was prospectively recorded in only 51% of attacks and mostly with mild intensity. The occurrence and severity of nausea was reduced with advancing patient age. Phonophobia was not consistently recorded in conjunction with photophobia.
Conclusion
These findings are consistent with variable involvement of different brain regions during a migraine attack. The variable occurrence of nausea, and phonophobia in conjunction with photophobia, both defining features of migraine, may be an important consideration in designing clinical studies of migraine in which prospectively recorded attacks are diagnosed based on these clinical features.
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Burgos-Vega, C. C., Ahn, D. D.-U., Bischoff, C., Wang, W., Horne, D., Wang, J., Gavva, N., Dussor, G., 2015-10-07 07:57:36 AM
Background
Migraine headache is a neurological disorder affecting millions worldwide. However, little is known about the mechanisms contributing to migraine. Recent genome-wide association studies have found single nucleotide polymorphisms in the gene encoding transient receptor potential channel M8. Transient receptor potential channel M8 is generally known as a cold receptor but it has been implicated in pain signaling and may play a role in migraine pain.
Methods
In order to investigate whether transient receptor potential channel M8 may contribute to the pain of migraine, the transient receptor potential channel M8 activator icilin was applied to the dura mater using a rat behavioral model of headache. Cutaneous allodynia was measured for 5 hours using Von Frey filaments.
Results
: Dural application of icilin produced cutaneous facial and hind paw allodynia that was attenuated by systemic pretreatment with the transient receptor potential channel M8-selective antagonist AMG1161 (10 mg/kg p.o.). Further, the anti-migraine agent sumatriptan (0.6 mg/kg s.c.) or the non-selective NOS inhibitor L-NAME (20 mg/kg i.p.) also attenuated allodynia when given as a pretreatment.
Conclusions
These data indicate that transient receptor potential channel M8 activation in the meninges produces behaviors in rats that are consistent with migraine and that are sensitive to pharmacological mechanisms known to have efficacy for migraine in humans. The findings suggest that activation of meningeal transient receptor potential channel M8 may contribute to the pain of migraine.
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Bourvis, N., Franc, J., Szatmary, Z., Chabriat, H., Crassard, I., Ducros, A., 2015-10-07 07:57:36 AM
Introduction
Reversible cerebral constriction syndrome and cerebral venous thrombosis are two rare conditions. Reversible cerebral constriction syndrome affects the cerebral arteries and the pathology is still largely unknown. To date, no physiological link with cerebral venous thrombosis has been reported.
Case results
We report here the case of a 24-year-old woman who presented a reversible cerebral constriction syndrome in the setting of a cerebral venous thrombosis. Cerebral venous thrombosis had developed in her left lateral venous sinus, within the stent placed one year before, in order to treat an idiopathic intracranial hypertension.
Discussion
The co-occurrence of cerebral venous thrombosis and reversible cerebral constriction syndrome in the same patient raises the issue of a potential link between them. We discuss the potential common trigger factors in this case: recent hormonal therapy; intracranial hypotension iatrogenically induced by lumbar puncture.
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Gottschalk, P. C. H., 2015-10-07 07:57:36 AM
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Amemiya, S., Takahashi, K., Mima, T., Yoshioka, N., Miki, S., Ohtomo, K., 2015-10-07 07:57:36 AM
Aim
The aim of this article is to investigate the pathophysiology underlying the alternation of the cognitive function and neuronal activity in spontaneous intracranial hypotension (SIH).
Methods
Fifteen patients with SIH underwent resting-state functional magnetic resonance imaging and working-memory (WM) test one day before and one month after a surgical operation. Alternation of the cognitive function and spontaneous neuronal activity measured as amplitude of the low-frequency fluctuations (ALFF) and the functional connectivity of the default-mode network (DMN) and frontoparietal networks (FPNs) were evaluated.
Results
WM performance significantly improved post-operatively. Whole-brain linear regression analysis of the ALFF revealed a positive correlation between cognitive performance change and ALFF change in the precuneus while a negative correlation was found in the bilateral orbitofrontal cortices (OFCs) and right medial frontal cortex (MFC). The ALFF changes normalised with the WM performance improvement post-operatively. The FPN activity in the right OFC was also increased pre-operatively. Partial correlation analysis revealed a significant correlation between WM performance and right OFC activity controlled for right FPN activity.
Conclusions
The abnormal activity of the OFCs and MFC that is not originating from the synchronous intrinsic network activity, together with the decreased activity of the central node of the DMN, could lead to cognitive impairment in SIH that is reversible through restoration of the cerebrospinal fluid.
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Hansen, E. K., Guo, S., Ashina, M., Olesen, J., 2015-10-07 07:57:36 AM
Background
A model for the testing of novel antimigraine drugs should ideally use healthy volunteers for ease of recruiting. Cilostazol provokes headache in healthy volunteers with some migraine features such as pulsating pain quality and aggravation by physical activity. Therefore, this headache might respond to sumatriptan, a requirement for validation. The hypothesis of the present study was that sumatriptan but not placebo is effective in cilostazol-induced headache in healthy individuals.
Methods
In a double-blind, randomized, cross-over design, 30 healthy volunteers of both sexes received cilostazol 200 mg on two separate days, each day followed by oral self-administered placebo or sumatriptan 50 mg. Headache response and accompanying symptoms were registered in a questionnaire by the participants themselves.
Results
Cilostazol induced a reproducible headache in 90% of the participants. The headache had several migraine-like features in most individuals. Median peak headache score was 2 on the sumatriptan day and 3 on the placebo day (p = 0.17). There was no reduction in headache intensity two hours after sumatriptan (p = 0.97) and difference in AUC 0 to four hours between two experimental days was not significant (p = 0.18). On the placebo day eight participants took rescue medication compared to 3 on the sumatriptan day (p = 0.13).
Conclusion
Despite similarities with migraine headache, cilostazol-induced headache in healthy volunteers does not respond to sumatriptan.
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Ho, T. W., Ho, A. P., Ge, Y., Assaid, C., Gottwald, R., MacGregor, E. A., Mannix, L. K., van Oosterhout, W. P., Koppenhaver, J., Lines, C., Ferrari, M. D., Michelson, D., 2015-10-07 07:57:36 AM
Aim
The aim of this article is to evaluate the safety and efficacy of perimenstrual telcagepant, a CGRP receptor antagonist, for headache prophylaxis.
Methods
We conducted a randomized, double-blind, placebo-controlled, six-month trial in women with migraine for ≥3 months who experienced perimenstrual headaches. Women were randomized to telcagepant 140 mg or placebo (2:1 ratio) for seven consecutive days perimenstrually. Safety was assessed by adverse events and laboratory tests. The primary efficacy endpoint was mean monthly headache days in the subset of women reporting perimenstrual migraine (–2 days to +3 days of menses onset) and ≥5 moderate or severe migraines per month prior to entering the trial.
Results
Telcagepant was generally well tolerated: 66/2660 (2.5%) on telcagepant and 36/1326 (2.7%) on placebo discontinued because of a clinical adverse event. The percentages of patients with clinical adverse events, laboratory adverse events, or discontinuation because of a laboratory adverse event were also similar between treatments. Alanine aminotransferase elevations ≥3x normal occurred in 0.6% of women on telcagepant and 0.4% on placebo. Three women on telcagepant vs none on placebo had alanine aminotransferase elevations ≥8xnormal. In the efficacy subset there was no significant effect of telcagepant (n = 887) vs placebo (n = 447) in mean monthly headache days (treatment difference –0.5 day (95% CI: –1.1, 0.1)). However, telcagepant was associated with a reduction in on-drug headache days (treatment difference –0.4 day (95% CI: –0.5, –0.2), nominal p < 0.001).
Conclusions
Telcagepant 140 mg taken perimenstrually for seven days was generally well tolerated, but was associated with transaminase elevations. Telcagepant did not reduce monthly headache frequency, but did reduce perimenstrual headaches.
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Tedeschi, G., Russo, A., Conte, F., Corbo, D., Caiazzo, G., Giordano, A., Conforti, R., Esposito, F., Tessitore, A., 2015-10-07 07:57:36 AM
Objective
To evaluate the resting-state visual network functional connectivity in patients with migraine with aura and migraine without aura during the interictal period.
Population and methods
Using resting-state functional magnetic resonance imaging, the resting-state visual network integrity was investigated in 20 patients with migraine with aura, 20 age- and sex-matched patients with migraine without aura and 20 healthy controls. Voxel-based morphometry and diffusion tensor imaging were used to assess whether between-groups differences in functional connectivity were dependent on structural or microstructural changes.
Results
Resting-state functional magnetic resonance imaging data showed that patients with migraine with aura, compared to both patients with migraine without aura and healthy controls, had a significant increased functional connectivity in the right lingual gyrus within the resting-state visual network (p < 0.05, cluster-level corrected). This abnormal resting-state visual network functional connectivity was observed in the absence of structural or microstructural abnormalities and was not related to migraine severity.
Conclusions
Our imaging data revealed that patients with migraine with aura exhibit an altered resting-state visual network connectivity. These results support the hypothesis of an extrastriate cortex involvement, centred in the lingual gyrus, a brain region related to mechanisms underlying the initiation and propagation of the migraine aura. This resting-state functional magnetic resonance imaging finding may represent a functional biomarker that could differentiate patients experiencing the aura phenomenon from patients with migraine without aura, even between migraine attacks.
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Bertolotto, A., Malentacchi, M., Capobianco, M., di Sapio, A., Malucchi, S., Motuzova, Y., Pulizzi, A., Berchialla, P., Sperli, F., 2015-10-07 07:57:36 AM
Objectives
The objectives of this article are to test the feasibility of lumbar puncture (LP) using 25-gauge (G) needles in daily neurological practice and to compare the risk of post-dural puncture headache (PDPH) with four types of needles.
Methods
In a prospective rater-blind study, pros and cons of four different LP needles, the 20G Quincke (20Q), 22G Sprotte (22S), 25G Whitacre (25W) and 25G Sprotte (25S), were evaluated in 394 LPs performed by seven neurologists. The neurologist performing the LP recorded the type and size of needle, intensity of pain, safety, time of the procedure and failure or success. Between five and 15 days later another neurologist, blind to the type of needle used, completed an ad-hoc questionnaire for PDPH.
Results
PDPH developed in 35.9% patients when using a 20Q needle, and in 12.9%, 6.8% and 1.6%, respectively, when using a 22S, 25W or 25S needle. The difference in incidence of PDPH following LP performed with the 20Q needle and the 25S or 22S was statistically significant (p < 0.001 and p = 0.008, respectively) and it approached significance when comparing the 25S and 25W (p = 0.06). As 25W and 25S needles need CSF aspiration, LP requires more time and skill. Pain caused by LP was similar with the four needles.
Conclusion
The use of the 25S needle in diagnostic LP reduces the frequency and severity of PDPH.
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Di Lorenzo, C., Coppola, G., Di Lorenzo, G., Bracaglia, M., Rossi, P., Pierelli, F., 2015-10-07 07:57:36 AM
Background
Cluster headache (CH) patients often receive unsatisfactory treatment and may explore illicit substances as alternatives. We aimed to explore this use of illicit drugs for CH treatment.
Methods
We invited CH patients from an Internet-based self-help group to complete a questionnaire regarding their therapeutic use of illicit substances.
Results
Of the 54 respondents, 29 were classified as chronic and 39 were drug-resistant cases. Fifty patients had previously tried subcutaneous sumatriptan, 40 had tried O2, and 48 had tried at least one prophylactic treatment. All 54 patients specified that they were dissatisfied with conventional treatments. Thirty-four patients had used cannabinoids, 13 cocaine, 8 heroin, 18 psilocybin, 12 lysergic acid amide (LSA), and 4 lysergic acid diethylamide (LSD).
Discussion
Some patients with intractable CH decided to try illicit drugs concomitantly with cessation of medical care. Most of these patients found suggestions for illicit drug use on the Internet. Many patients seemed to underestimate the judicial consequences of, and had an overestimated confidence in the safety of, such illicit treatments. Physicians are often not informed by patients of their choice to use illicit drugs. This leads to questions regarding the true nature of the physician-patient relationship among dissatisfied CH patients.
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Pijpers, J., Louter, M., de Bruin, M., van Zwet, E., Zitman, F., Ferrari, M., Terwindt, G., 2015-10-07 07:57:36 AM
Aim
The aim of this article is to determine whether support by a headache nurse in the treatment of medication-overuse headache (MOH) increases successful withdrawal, and to study determinants of response to withdrawal therapy.
Methods
A retrospective, controlled follow-up study was performed with 416 MOH patients. All patients were treated with outpatient withdrawal therapy, with two treatment arms: with or without the support of a specialised headache nurse. The outcome measures were: i) successful withdrawal, defined as discontinuation of all headache medication according to the study protocol; and ii) the responder rate, defined as the percentage of patients with ≥50% reduction in headache days after successful withdrawal and iii) relative reduction in headache days after successful withdrawal.
Results
Successful withdrawal percentages were significantly higher in the group supported by the headache nurse than in the group without support (73.1% vs. 60.7%; p = 0.008), which was confirmed in multivariate analysis (OR 1.73, 95% CI 1.11–2.71, p = 0.016). Support by a headache nurse was not associated with response. The underlying primary headache diagnosis, determined after withdrawal, was significantly correlated with response.
Conclusion
The support by a headache nurse results in an increased adherence to detoxification.
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Hansen, J. M., Larsen, V. A., Scheie, D., Perry, A., Skjoth-Rasmussen, J., 2015-10-07 07:57:36 AM
A 17-year-old female with migraine with aura complained of fatigue and was diagnosed with anemia. Three years later, changes in her headache pattern prompted hospital referral. Brain MRI showed a bi-lobed extra-axial intracerebral tumor encroaching both parieto-occipital regions. The resection specimen yielded a rare diagnosis of primary intracranial angiomatoid fibrous histiocytoma (AFH). Tumor removal resulted in cessation of her migraine and anemia. AFH may cause systemic symptoms – in this case fatigue and anemia – long before focal neurological symptoms are present. This is the first report of an intracranial AFH presenting as migraine with visual aura and anemia.
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Takizawa, T., Shibata, M., Fujiwara, H., Shimizu, T., Momoshima, S., Suzuki, N., 2015-10-07 07:57:36 AM
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Honningsvag, L.-M., Hagen, K., Haberg, A., Stovner, L. J., Linde, M., 2015-10-07 07:57:36 AM
Background
Most studies on intracranial abnormalities among headache sufferers were performed in selected clinical populations. The aim of this study was to evaluate the relationship between intracranial abnormalities and headache among middle-aged adults in the general population.
Methods
Participants in a large epidemiological study (the HUNT 3 study; 2006–2008) who answered a headache questionnaire and participated in a population-based imaging study of the head (HUNT MRI; 2007–2009) were included (n = 864; age, 50–65 at enrollment). Based on the responses to the HUNT 3 questionnaire, respondents were categorized as having migraine, tension-type headache, or unclassified headache. Logistic regression was used to compare the occurrence of intracranial abnormalities between groups.
Results
Intracranial abnormalities were more common in headache sufferers than in headache-free individuals (29% vs. 22%, respectively; p = 0.041). Adjusted multivariate analyses revealed that those with tension-type headache had higher odds of having minor abnormalities (odds ratio, 2.13; 95% confidence interval = 1.18–3.85). This association disappeared when those with only white matter hyperintensities were removed from the analysis.
Conclusions
Headache sufferers had increased odds of minor intracranial abnormalities. The increased odds were primarily related to the presence of white matter hyperintensities.
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Fang, L., Jingjing, L., Ying, S., Lan, M., Tao, W., Nan, J., 2015-10-07 07:57:36 AM
Background
Sphenopalatine ganglion percutaneous radiofrequency thermocoagulation treatment can improve the symptoms of cluster headaches to some extent. However, as an ablation treatment, radiofrequency thermocoagulation treatment also has side effects.
Objective
To preliminarily evaluate the efficacy and safety of a non-ablative computerized tomography-guided pulsed radiofrequency treatment of sphenopalatine ganglion in patients with refractory cluster headaches.
Methods
We included and analysed 16 consecutive cluster headache patients who failed to respond to conservative therapy from the Pain Management Center at the Beijing Tiantan Hospital between April 2012 and September 2013 treated with pulsed radiofrequency treatment of sphenopalatine ganglion.
Results
Eleven of 13 episodic cluster headaches patients and one of three chronic cluster headaches patient were completely relieved of the headache within an average of 6.3 ± 6.0 days following the treatment. Two episodic cluster headache patients and two chronic cluster headache patients showed no pain relief following the treatment. The mean follow-up time was 17.0 ± 5.5 months. All patients enrolled in this study showed no treatment-related side effects or complications.
Conclusion
Our data show that patients with refractory episodic cluster headaches were quickly, effectively and safely relieved from the cluster period after computerized tomography-guided pulsed radiofrequency treatment of sphenopalatine ganglion, suggesting that it may be a therapeutic option if conservative treatments fail.
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Niddam, D. M., Lai, K.-L., Fuh, J.-L., Chuang, C.-Y. N., Chen, W.-T., Wang, S.-J., 2015-10-07 07:57:36 AM
Background
Migraine with visual aura (MA) is associated with distinct visual disturbances preceding migraine attacks, but shares other visual deficits in between attacks with migraine without aura (MO). Here, we seek to determine if abnormalities specific to interictal MA patients exist in functional brain connectivity of intrinsic cognitive networks. In particular, these networks are involved in top-down modulation of visual processing.
Methods
Using resting-state functional magnetic resonance imaging, whole-brain functional connectivity maps were derived from seeds placed in the anterior insula and the middle frontal gyrus, key nodes of the salience and dorsal attention networks, respectively. Twenty-six interictal MA patients were compared with 26 matched MO patients and 26 healthy matched controls.
Results
The major findings were: connectivity between the anterior insula and occipital areas, including area V3A, was reduced in MA but not in MO. Connectivity changes between the anterior insula and occipital areas further correlated with the headache severity in MA only.
Conclusions
The unique pattern of connectivity changes found in interictal MA patients involved area V3A, an area previously implicated in aura generation. Hypoconnectivity to this and other occipital regions may either represent a compensatory response to occipital dysfunctions or predispose MA patients to the development of aura.
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Abu Bakar, N., Tanprawate, S., Lambru, G., Torkamani, M., Jahanshahi, M., Matharu, M., 2015-10-07 07:57:36 AM
Background
Health-related quality of life (HRQoL) is emerging as an important element of clinical research in primary headache disorders, allowing a measure of the impact of headache on patients' well-being and daily life. A better understanding of this may contribute to improved resource allocations and treatment approaches.
Objective
The objective of this study is to review available data on HRQoL in primary headache disorders and identify any influencing factors.
Methods
Database searches including MEDLINE, PsycINFO and EMBASE were performed. Studies that investigated HRQoL in patients with primary headache disorders were included and reviewed. Trials that evaluated the efficacy of medications or interventions were excluded.
Results
A total of 80 articles were included in the review. Both physical and emotional/mental aspects of HRQoL were impaired across headache subtypes, although the extent varied depending on headache type. A number of factors influencing HRQoL were also identified.
Conclusion
This narrative review suggests that headache, particularly in its chronic form, has a great impact on HRQoL. Clinical practice should not solely focus on pain alleviation but rather adopt routine assessment of HRQoL. Furthermore, identification and management of associated psychological comorbidities, which can significantly influence HRQoL in headache sufferers, are essential for optimal clinical management.
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Takizawa, T., Shibata, M., Kayama, Y., Toriumi, H., Ebine, T., Koh, A., Shimizu, T., Suzuki, N., 2015-10-07 07:57:36 AM
Introduction
Cortical spreading depression (CSD) has recently been shown to induce the release of the nuclear protein termed high-mobility group box 1 from neurons, causing activation of the trigeminovascular system. Here, we explored the effects of single and multiple cortical spreading depression inductions on high-mobility group box 1 (HMGB1) transcriptional activity relative to high-mobility group box 1 protein expression levels and intracellular localization in cortical neurons and astrocytes.
Methods
Single or multiple cortical spreading depression inductions were achieved by KCl application to the mouse cerebral cortex. The animals were sacrificed at 30 minutes, 3 hours and 24 hours after cortical spreading depression induction. High-mobility group box 1 expression levels were explored with in situ hybridization, Western blotting and immunostaining.
Results
Cortical spreading depression up-regulated high-mobility group box 1 transcriptional activity in neurons at 3 hours in a manner that was dependent on the number of cortical spreading depression inductions. At 24 hours, thehigh-mobility group box 1 transcriptional activity had returned to basal levels. Cortical spreading depression induced a reduction in high-mobility group box 1 protein expression at 3 hours, which was also dependent on the number of cortical spreading depression inductions. Following cortical spreading depression, the release of high-mobility group box 1 from the nucleus was observed in a small proportion of neurons, but not in astrocytes.
Conclusion
Cortical spreading depression induced translocation of high-mobility group box 1 from neuronal nuclei, driving transcriptional up-regulation of high-mobility group box 1 to maintain protein levels.
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Altiokka, O., Mutluay, B., Koksal, A., Ciftci-Kavaklioglu, B., Ozturk, M., Altunkaynak, Y., Baybas, S., Soysal, A., 2015-10-07 07:57:36 AM
Objective
To investigate which part of the autonomic system is mainly involved and assess the sensitivity of face sympathetic skin response in cluster headache.
Material and methods
The study sample consisted of 19 drug-free cluster headache patients (16 males, three females) and 19 healthy volunteers. Demographic features and pain characteristics were thoroughly identified. Dysautonomic symptoms were evaluated during attack and remission periods of cluster headache patients. Orthostatic hypotension, R-R interval variation and sympathetic skin responses obtained from the face and four extremities were evaluated and the sensitivity of face sympathetic skin responses was assessed in contrast to extremity sympathetic skin responses.
Results
All sympathetic skin responses of face and extremities could be obtained during attack and remission periods. On the symptomatic side, mean latency of face sympathetic skin responses was longer compared to the asymptomatic side and controls (p = 0.02, p = 0.004). There were no differences in latency or amplitude of extremity sympathetic skin responses between symptomatic and asymptomatic sides and controls. No significant relationship was determined between sympathetic skin responses, R-R interval variation, orthostatic hypotension and cluster headache clinical features.
Conclusion
Sympathetic hypoactivity of the face seems to predominate the pathophysiology of cluster headache. Face sympathetic skin responses might be more sensitive compared to extremity sympathetic skin response in demonstrating dysautonomic symptoms in cluster headache patients.
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de Coo, I. F., Wilbrink, L. A., Haan, J., 2015-10-07 07:57:36 AM
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Madsen, B. K., Sogaard, K., Andersen, L. L., Skotte, J. H., Jensen, R. H., 2015-10-07 07:57:36 AM
Introduction
Tension-type headache (TTH) is highly prevalent in the general population, and it is characterized by increased muscle tenderness with increasing headache frequency and intensity.
Aim
The aim of this case-control study was to compare muscle strength in neck and shoulder muscles in TTH patients and healthy controls by examining maximal voluntary isometric contraction (MVC) during shoulder abduction, neck flexion and extension as well as the extension/flexion strength ratio of the neck.
Methods
Sixty TTH patients and 30 sex- and age-matched healthy controls were included. Patients were included if they had TTH ≥8 days per month. The MVC neck extensor and flexor muscles were tested with the participant seated upright. MVC shoulder abduction was tested with the individual lying supine.
Results
Compared to controls TTH patients had significantly weaker muscle strength in neck extension (p = 0.02), resulting in a significantly lower extension/flexion moment ratio (p = 0.03). TTH patients also showed a tendency toward significantly lower muscle strength in shoulder abduction (p = 0.05). Among the 60 TTH patients, 25 had frequent episodic TTH (FETTH), and 35 had chronic TTH (CTTH).
Conclusion
Patients with TTH exhibited decreased muscle strength in the neck extensor muscles, inducing a reduced cervical extension/flexion ratio compared to healthy people.
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Westergaard, M. L., Glumer, C., Hansen, E. H., Jensen, R. H., 2015-10-07 07:57:36 AM
Aim
This cross-sectional study investigated associations between chronic headache (CH) with and without medication overuse, healthy lifestyle behaviour, and stress.
Methods
Questionnaires were sent to 129,150 adults. Those with headache ≥15 days per month for three months were classified as having CH then further described as having medication-overuse headache (MOH) or CH without medication overuse. Associations between headache and daily smoking, physical inactivity, obesity, excessive drinking, illicit drug use, and high stress were analysed by logistic regression.
Results
CH with and without medication overuse (prevalence 1.8% and 1.6%, respectively) had strong, graded associations with stress. Associations with daily smoking, physical inactivity, and obesity were significant only for MOH. Odds for MOH were highest among people who had all three factors compared to those who had none (OR 2.8 in women and 5.1 in men). High stress plus any of these three factors had synergistic effects in MOH but not clearly in those who had CH without overuse. Associations between CH subtypes and excessive drinking or illicit drug use were not statistically significant.
Conclusion
Results suggest strong links between healthy lifestyle behaviour and stress in MOH. Stress reduction and promoting healthy behaviour are highly relevant in MOH management.
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Messina, R., Rocca, M. A., Colombo, B., Pagani, E., Falini, A., Comi, G., Filippi, M., 2015-10-07 07:57:36 AM
Background
Diffusion tensor (DT) magnetic resonance imaging (MRI) provides several quantities with the potential to disclose white matter (WM) microstructural abnormalities. We explored alterations of WM architecture in pediatric migraine patients using DT MRI and two different methods of analysis.
Methods
Dual-echo and DT MRI scans were acquired from 15 pediatric migraine patients and 15 age-matched controls. Whole-brain voxel-wise comparisons of WM DT MRI abnormalities were performed using tract-based-spatial-statistics (TBSS). A DT probabilistic tractography analysis was also run.
Results
Both TBSS and DT tractography analysis showed that, compared to controls, pediatric migraine patients had significant lower mean (MD), axial (AD) and radial (RD) diffusivity of WM tracts located in the brainstem, thalamus and fronto-temporo-occipital lobes, bilaterally. Patients also experienced increased fractional anisotropy (FA) of the optic radiations. No correlation was found between WM tract abnormalities and disease duration and attack frequency.
Conclusions
Pediatric migraine patients harbor diffuse brain WM microstructural abnormalities. High FA and low MD, AD and RD in these patients might be explained by repeated neuronal activation, which may lead to cell swelling and stimulate activity-dependent myelin-modulation, or by increased fiber and dendritic densities. Both these mechanisms might reflect a hyperexcitability of the brain in migraineurs.
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Pozo-Rosich, P., Storer, R., Charbit, A., Goadsby, P., 2015-10-07 07:57:36 AM
Background
Calcitonin gene-related peptide (CGRP) receptor antagonism is an approach to migraine therapy. The locus of action of antimigraine treatment is not resolved. The objective was to investigate CGRP receptors in the ventrolateral periaqueductal gray (vlPAG) involved in the modulation of trigeminovascular nociception by descending influences on neurotransmission.
Methods
The presence of calcitonin receptor-like receptor (CLR) and receptor activity modifying protein 1 (RAMP1), which form functional CGRP receptors, was investigated. CGRP and its receptor antagonists, olcegepant and CGRP (8–37), were microinjected into the vlPAG while changes of neural responses in the trigeminocervical complex (TCC) were monitored.
Results
Immunoreactivity indicated the presence of functional CGRP receptor components in the vlPAG and adjacent mesencephalic trigeminal nucleus. Inhibition of TCC responses to stimulation of dural afferents and ophthalmic cutaneous receptive fields after microinjection of bicuculline into vlPAG indicated a connection between the vlPAG and TCC neurons. CGRP facilitated these TCC responses, whereas olcegepant and CGRP (8–37) decreased them.
Conclusions
CGRP and its receptor antagonists act on neurons in the region of vlPAG to influence nociceptive transmission in the TCC. This suggests CGRP receptor antagonists may act at loci outside of the TCC and reinforces the concept of migraine as a disorder of the brain.
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Pareja, J. A., Casanova, I., Arbex, A., Cuadrado, M. L., 2015-10-07 07:57:36 AM
Introduction
The infratrochlear nerve supplies the medial aspect of the upper eyelid, the superolateral aspect of the nose and the lacrimal caruncle. This nerve may contribute to the pain stemming from the trochlea, but infratrochlear neuralgia has not been identified as a specific cause of pain.
Methods
Over a 10-year period we have been recruiting patients with pain in the internal angle of the orbit that did not show features of trochlear pain.
Results
Seven patients (six female, one male; mean age, 46.1 ± 18.9) presented with pain in the territory of the infratrochlear nerve. The pain appeared in the internal angle of the orbit and upper eyelid (n = 3), the superolateral aspect of the nose (n = 3), or the lacrimal caruncle (n = 1). All patients had a paroxysmal pain, with the attacks lasting five to 30 seconds. Pain attacks were mostly spontaneous, but two patients had triggers. Between attacks, all patients had local allodynia. Pain did not increase with vertical eye movements. Six patients were treated with gabapentin with complete response, and one patient experienced long-lasting relief with an anesthetic blockade of the infratrochlear nerve.
Conclusion
Infratrochlear neuralgia should be considered as a possible cause of pain in the internal angle of the orbit.
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Nguyen, B. N., McKendrick, A. M., Vingrys, A. J., 2015-10-07 07:57:36 AM
Background
People with migraine show increased surround suppression of perceived contrast, a perceptual analogue of centre-surround antagonistic interactions in visual cortex. A proposed mechanism is that cortical 'hyperexcitability' or 'hyperresponsivity', a prominent theory in the migraine literature, drives abnormal excitatory-inhibitory balance to give increased local inhibition. The purpose of this cross-sectional study was to determine whether cortical hyperresponsivity and excitatory-inhibitory imbalance manifests in the visual cortical response of migraine sufferers.
Methods
Interictal steady-state visual evoked potentials (VEPs) in response to 0 to 97% contrast were recorded in 30 migraine participants (15 without aura, 15 with aura) and 21 non-headache controls. Monotonicity indices were calculated to determine response saturation or supersaturation. Contrast gain was modelled with a modified saturating hyperbolic function to allow for variation in excitation and inhibition.
Results
A greater proportion of migraine participants (43%) than controls (14%) exhibited significant VEP supersaturation at high contrast, based on monotonicity index (chi-square, p = 0.028). Supersaturation was also evident by the trend for greater suppressive exponent values in migraine compared to control individuals (Mann-Whitney rank sum, p = 0.075).
Conclusions
Supersaturation in migraine is consistent with excess excitation (hyperresponsivity) driving increased network inhibition and provides support for excitatory-inhibitory imbalance as a pathophysiological disturbance in migraine.
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Barloese, M., Brinth, L., Mehlsen, J., Jennum, P., Lundberg, H. I. S., Jensen, R., 2015-10-07 07:57:36 AM
Background
Cluster headache (CH) is a disabling headache disorder with chronobiological features. The posterior hypothalamus is involved in CH pathophysiology and is a hub for autonomic control. We studied autonomic response to the head-up tilt table test (HUT) including heart rate variability (HRV) in CH patients and compared results to healthy controls.
Methods and materials
Twenty-seven episodic and chronic CH patients and an equal number of age-, sex- and BMI-matched controls were included. We analyzed responses to HUT in the time and frequency domain and by non-linear analysis.
Results
CH patients have normal cardiovascular responses compared to controls but increased blood pressure. In the frequency analysis CH patients had a smaller change in the normalized low- (LF) (2.89 vs. 13.38, p < 0.05) and high-frequency (HF) (–2.86 vs. –13.38, p < 0.05) components as well as the LF/HF ratio (0.81 vs. 2.62, p < 0.05) in response to tilt. In the Poincaré plot, the change in ratio between long- and short-term variation was lower in patients (SD1/SD2, –0.05 vs. –0.17, p < 0.05).
Conclusions
CH patients show decreased autonomic response to HUT compared to healthy controls. This can be interpreted as dysregulation in the posterior hypothalamus and supports a theory of central autonomic mechanisms involvement in CH.
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Kageyama, T., Isohisa, A., Mori, N., Suenaga, T., 2015-10-07 07:57:36 AM
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Sillanpaa, M., Saarinen, M., 2015-10-07 07:57:36 AM
Purpose
To explore the association between infantile colic and adolescent migraine.
Method
In a randomized general population sample, families expecting their first child were prospectively followed for infantile colic and adolescent migraine.
Results
Colic was diagnosed in 160 (13%) of 1267 infants until the age of 3 months. Migraine was ascertained in 129 (16%) of 787 adolescents at age 18 years. History of infantile colic was identified in 96 (12%) of 787 adolescents and no such history in 658 (88%) of 787 adolescents. Migraine was present in 22 (23%)/96 adolescents who had a history of infantile colic, but in only 74 (11%)/658 ones who had no such history. Of the 22 adolescents, 14 (64%) had migraine without aura and eight (36%) had migraine with aura. Infants with colic had an almost three-fold risk (risk ratio 2.8, 95% confidence interval 1.2–6.5) for adolescent migraine without aura, but no increased risk for migraine with aura (0.8, 0.3–2.2).
Discussion and conclusions
Infantile colic seems to be associated with an increased risk for migraine without aura, but not for migraine with aura. Whether infantile colic per se is a type of infantile migraine or an antecedent of future migraine remains to be answered by further research.
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Gelfand, A. A., Fullerton, H. J., Jacobson, A., Sidney, S., Goadsby, P. J., Kurth, T., Pressman, A., 2015-10-07 07:57:36 AM
Importance
Our understanding of risk factors for childhood stroke is incomplete. In adults, migraine with aura is associated with a two-fold increase in ischemic stroke risk.
Objective
In this cohort study we examine the association between migraine and stroke among children in Kaiser Permanente Northern California (KPNC).
Design, setting, and participants
Children ages 2–17 years who were members of KPNC for ≥6 months between 1997 and 2007 were included. Migraine cohort members had one or more of: an ICD-9 code for migraine, migraine listed as a significant health problem, or a prescription for a migraine-specific medication. The comparison group was children with no evidence of headache.
Main outcome measures
Main outcome measures included stroke incidence rates and incidence rate ratios (IR).
Results
Among the 1,566,952 children within KPNC during the study period, 88,164 had migraine, and 1,323,142 had no evidence of headache. Eight migraineurs had a stroke (three (38%) hemorrhagic; five (63%) ischemic). Eighty strokes occurred in children without headache (53 (66%) hemorrhagic; 27 (34%) ischemic). The ischemic stroke incidence rate was 0.9/100,000 person-years in migraineurs vs. 0.4/100,000 person-years in those without headache; IR 2.0 (95% CI 0.8–5.2). A post-hoc analysis of adolescents (12–17 years) showed an increased risk of ischemic stroke among those with migraine; IR 3.4 (95% CI 1.2–9.5). The hemorrhagic stroke incidence rate was 0.5/100,000 person-years in migraineurs and 0.9/100,000 person-years in those without headache; IR 0.6 (95% CI 0.2–2.0).
Conclusions
There was no statistically significant increase in hemorrhagic or ischemic stroke risk in pediatric migraineurs in this cohort study. A post-hoc analysis found that ischemic stroke risk was significantly elevated in adolescents with migraine. Future studies should focus on identifying risk factors for ischemic stroke among adolescent migraineurs. Based on adult data, we recommend that migraine aura status should be studied as a possible risk factor for ischemic stroke among adolescent migraineurs.
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Vetvik, K. G., Benth, J. Šaltyte, MacGregor, E. A., Lundqvist, C., Russell, M. B., 2015-10-07 07:57:36 AM
Objective
The objective of this article is to compare clinical characteristics of menstrual and non-menstrual attacks of migraine without aura (MO), prospectively recorded in a headache diary, by women with and without a diagnosis of menstrual migraine without aura (MM) according to the International Classification of Headache Disorders (ICHD).
Material and methods
A total of 237 women from the general population with self-reported migraine in ≥50% of their menstrual periods were interviewed and classified by a physician according to the criteria of the ICHD II. Subsequently, all participants were instructed to complete a prospective headache diary for at least three menstrual cycles. Clinical characteristics of menstrual and non-menstrual attacks of MO were compared by a regression model for repeated measurements.
Results
In total, 123 (52%) women completed the diary. In the 56 women who were prospectively diagnosed with MM by diary, the menstrual MO-attacks were longer (on average 10.65 hours, 99% CI 3.17–18.12) and more frequently accompanied by severe nausea (OR 2.14, 99% CI 1.20–3.84) than non-menstrual MO-attacks. No significant differences between menstrual and non-menstrual MO-attacks were found among women with MO, but no MM.
Conclusion
In women from the general population, menstrual MO-attacks differ from non-menstrual attacks only in women who fulfil the ICHD criteria for MM.
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Mesa-Jimenez, J. A., Lozano-Lopez, C., Angulo-Diaz-Parreno, S., Rodriguez-Fernandez, A. L., De-la-Hoz-Aizpurua, J. L., Fernandez-de-las-Penas, C., 2015-10-07 07:57:36 AM
Background
Manual therapies are generally requested by patients with tension type headache.
Objective
To compare the efficacy of multimodal manual therapy vs. pharmacological care for the management of tension type headache pain by conducting a meta-analysis of randomized controlled trials.
Methods
PubMed, MEDLINE, EMBASE, AMED, CINAHL, EBSCO, Cochrane Database of Systematic Reviews, Cochrane Collaboration Trials Register, PEDro and SCOPUS were searched from their inception until June 2014. All randomized controlled trials comparing any manual therapy vs. medication care for treating tension type headache adults were included. Data were extracted and methodological quality assessed independently by two reviewers. We pooled headache frequency as the main outcome and also intensity and duration. The weighted mean difference between manual therapy and pharmacological care was used to determine effect sizes.
Results
Five randomized controlled trials met our inclusion criteria and were included in the meta-analysis. Pooled analyses found that manual therapies were more effective than pharmacological care in reducing frequency (weighted mean difference –0.8036, 95% confidence interval –1.66 to –0.44; three trials), intensity (weighted mean difference –0.5974, 95% confidence interval –0.8875 to –0.3073; five trials) and duration (weighted mean difference –0.5558, 95% confidence interval –0.9124 to –0.1992; three trials) of the headache immediately after treatment. No differences were found at longer follow-up for headache intensity (weighted mean difference –0.3498, 95% confidence interval –1.106 to 0.407; three trials).
Conclusion
Manual therapies were associated with moderate effectiveness at short term, but similar effectiveness at longer follow-up for reducing headache frequency, intensity and duration in tension type headache than pharmacological medical drug care. However, due to the heterogeneity of the interventions, these results should be considered with caution at this stage.
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Schulte, L., May, A., 2015-10-07 07:57:36 AM
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Ambrosini, A., D'Alessio, C., Magis, D., Schoenen, J., 2015-10-07 07:57:36 AM
Background
Migraine is a highly prevalent neurological disorders and a major individual and societal burden. Migraine is not curable at the present time, but it is amenable to acute symptomatic and preventive pharmacotherapies.
Summary
Since the latter are frequently unsatisfactory, other treatment strategies have been used or are being explored. In particular, interventions targeting pericranial nerves are now part of the migraine armamentarium. We will critically review some of them, such as invasive and noninvasive neurostimulation, therapeutic blocks and surgical decompressions.
Conclusions
Although current knowledge on migraine pathophysiology suggests a central nervous system dysfunction, there is some evidence that interventions targeting peripheral nerves are able to modulate neuronal circuits involved in pain control and that they could be useful in some selected patients. Larger, well-designed and comparative trials are needed to appraise the respective advantages, disadvantages and indications of most interventions discussed here.
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Gelfand, A. A., 2015-10-07 07:57:36 AM
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Pedersen, S. H., Ramachandran, R., Amrutkar, D. V., Petersen, S., Olesen, J., Jansen-Olesen, I., 2015-10-07 07:57:36 AM
Background
Migraine patients develop attacks several hours after intravenous infusion of glyceryl trinitrate. Due to the short half-life of nitric oxide, this delayed migraine cannot be caused by a direct action of nitric oxide derived from glyceryl trinitrate. The involvement of meningeal inflammation and dural mast cell degranulation is supported by the effectiveness of prednisolone on glyceryl trinitrate-induced delayed headache.
Methods
Using a newly developed rat model mimicking the human glyceryl trinitrate headache model, we have investigated the occurrence of dural mast cell degranulation after a clinically relevant dose of glyceryl trinitrate.
Results
A 6-fold increase in degranulation was observed starting at 2 hours after glyceryl trinitrate infusion. Interestingly, pre-treatment with the effective anti-migraine substances L-nitro-arginine methyl ester and sumatriptan prevented glyceryl trinitrate-induced mast cell degranulation whereas the calcitonin gene-related peptide-receptor antagonist olcegepant and the substance P receptor antagonist L-733,060 did not affect mast cell degranulation. However, topical application of two different nitric oxide donors did not cause mast cell degranulation ex vivo.
Conclusions
Direct application of an exogenous nitric oxide donor on dural mast cells does not cause mast cell degranulationex vivo. In vivo application of the nitric oxide donor glyceryl trinitrate leads to a prominent level of degranulation via a yet unknown mechanism. This effect can be completely blocked by inhibition of the endogenous nitric oxide production and by 5-HT1B/1D receptor agonists but is unaffected by calcitonin gene-related peptide and substance P receptor antagonists.
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Kunkler, P. E., Zhang, L., Pellman, J. J., Oxford, G. S., Hurley, J. H., 2015-10-07 07:57:36 AM
Background
Air pollution is linked to increased emergency room visits for headache, and migraine patients frequently cite chemicals or odors as headache triggers, but the association between air pollutants and headache is not well understood. We previously reported that nasal administration of environmental irritants acutely increases meningeal blood flow via a TRPA1-dependent mechanism involving the trigeminovascular system. Here, we examine whether chronic environmental irritant exposure sensitizes the trigeminovascular system.
Methods
Male rats were exposed to acrolein, a TRPA1 agonist, or room air by inhalation for four days prior to meningeal blood flow measurements. Some animals were injected daily with a TRPA1 antagonist, AP-18, or vehicle prior to inhalation exposure. Trigeminal ganglia were isolated following blood flow measurements for immunocytochemistry and/or qPCR determination of TRPV1, TRPA1 and CGRP levels.
Results
Acrolein inhalation exposure potentiated blood flow responses both to TRPA1 and TRPV1 agonists compared to room air. Acrolein exposure did not alter TRPV1 or TRPA1 mRNA levels or TRPV1 or CGRP immunoreactive cell counts in the trigeminal ganglion. Acrolein sensitization of trigeminovascular responses to a TRPA1 agonist was attenuated by pre-treatment with AP-18.
Interpretation
These results suggest trigeminovascular sensitization as a mechanism for enhanced headache susceptibility after chemical exposure.
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Beams, J. L., Kline, M. T., Rozen, T. D., 2015-10-07 07:57:36 AM
Objective
The objective of this research is to describe novel procedural treatments for hemicrania continua that allow patients to remain off indomethacin.
Methods
Case reports are presented.
Results
We describe four distinct patients with indomethacin-responsive hemicrania continua who were unable to discontinue the use of indomethacin without headache recurrence. No other medications were effective for their syndrome. Secondary causes of headache were ruled out in each case. Each patient underwent diagnostic blockade of either the atlanto-axial joint, C2 dorsal root ganglion or sphenopalantine ganglion depending on their clinical examination and presence of cranial autonomic symptoms. A positive response led to a radiofrequency ablation of the C2 ventral ramus, C2 dorsal root ganglion or sphenopalantine ganglion, which provided headache relief in all case patients as complete as indomethacin. Long-term follow-up of these patients has shown that all have remained essentially headache free without the need for indomethacin. One patient has needed repeat radiofrequency procedures with consistent response.
Conclusion
Hemicrania continua is defined by its sensitivity to indomethacin but very few patients are able to discontinue the medication without headache recurrence. As the risks of chronic indomethacin use are substantial, alternative treatments are necessary to protect patient health. We are now able to suggest several radiofrequency ablation procedures as effective as indomethacin with long-term follow-up.
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Krogh, A.-B., Larsson, B., Linde, M., 2015-10-07 07:57:36 AM
Background
Headache is common in adolescents and affects schoolwork and relations with friends and family. In most previous epidemiological surveys, only the most bothersome headache has been documented. The aim was to determine headache prevalence not only taking into account the most bothersome headache, but also to compare characteristics of the most bothersome and less bothersome headaches, and to investigate headache-related disability.
Methods
A cross-sectional school-based study was conducted in which 493 representative adolescents aged 12–18 years were recruited by stratified cluster sampling and interviewed. Headache diagnosis was made according to the new classification system of the International Headache Society (ICHD-3 beta), and the Pediatric Migraine Disability Assessment (PedMIDAS) was used to evaluate disability.
Results
The one-year prevalence of any headache type, definite migraine, probable migraine and tension-type headache was 88%, 23%, 13% and 58%, respectively. The point prevalence of any headache was 38%. Nine percent of participants fulfilled criteria for more than one headache diagnosis. The most bothersome headache had a significantly longer duration (p < 0.001) and higher intensity (p < 0.001) than the less bothersome headache, but similar frequency (p = 0.86). Adolescents with headaches lost up to nine days of activity each year, implicating headache as a major health issue.
Conclusions
Headaches are very common and disabling among adolescents. The full extent of this health problem is better appreciated if inquiry is not limited to the most bothersome subtypes.
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Chong, C. D., Schwedt, T. J., 2015-10-07 07:57:36 AM
Background
Specific white-matter tract alterations in migraine remain to be elucidated. Using diffusion tensor imaging (DTI), this study investigated whether the integrity of white-matter tracts that underlie regions of the "pain matrix" is altered in migraine and interrogated whether the number of years lived with migraine modifies fibertract structure.
Methods
Global probabilistic tractography was used to assess the anterior thalamic radiations, the corticospinal tracts and the inferior longitudinal fasciculi in 23 adults with migraine and 18 healthy controls.
Results
Migraine patients show greater mean diffusivity (MD) in the left and right anterior thalamic radiations, the left corticospinal tract, and the right inferior longitudinal fasciculus tract. Migraine patients also show greater radial diffusivity (RD) in the left anterior thalamic radiations, the left corticospinal tract as well as the left and right inferior longitudinal fasciculus tracts. No group fractional anisotropy (FA) differences were identified for any tracts. Migraineurs showed a positive correlation between years lived with migraine and MD in the right anterior thalamic radiations (r = 0.517; p = 0.012) and the left corticospinal tract (r = 0.468; p = 0.024).
Conclusion
Results indicate that white-matter integrity is altered in migraine and that longer migraine history is positively correlated with greater alterations in tract integrity.
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Frishberg, B., 2015-10-07 07:57:36 AM
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Altıokka-Uzun, G., Tuzun, E., Ekizoğlu, E., Ulusoy, C., Yentur, S., Kurtuncu, M., Saruhan-Direskeneli, G., Baykan, B., 2015-10-07 07:57:36 AM
Objectives
The pathogenesis of idiopathic intracranial hypertension (IIH) is currently unknown and there are speculations about the contribution of some immunologic factors. The aim of this study is to investigate the presence of oligoclonal bands (OCBs) and cerebrospinal fluid (CSF) and/or serum cytokine levels in patients with IIH.
Methods
Patients fulfilling revised diagnostic criteria for IIH were included. Their demographic, clinical, ophthalmologic and laboratory features were examined. Serum and CSF samples were detected by isoelectric focusing and immunoblotting for OCBs. The samples of IIH patients and control groups were investigated by ELISA for cytokine levels.
Results
We detected OCBs in eight (30.77%) patients diagnosed with IIH. There were no other obvious clinical and laboratory differences of IIH profiles between the patients with and without OCBs, but frequency of vision loss was significantly higher in the group with OCBs in comparison to OCB negatives (p = 0.038). Patients with IIH had highly elevated TNF-α, IFN-, IL-4, IL-10, IL-12, IL-17 in their sera compared to patients with multiple sclerosis (MS) and healthy controls. Furthermore, all cytokines except TNF-α in the CSF were found significantly higher in IIH patients compared to MS controls.
Conclusion
The presence of OCBs and elevated cytokine levels in IIH patients may support an immunologic background in the pathophysiological pathway of this disorder.
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Callaghan, B. C., Kerber, K. A., Pace, R. J., Skolarus, L., Cooper, W., Burke, J. F., 2015-10-07 07:57:36 AM
Aims
The aim of this article is to determine the patient-level factors associated with headache neuroimaging in outpatient practice.
Methods
Using data from the 2007–2010 National Ambulatory Medical Care Surveys (NAMCS), we estimated headache neuroimaging utilization (cross-sectional). Multivariable logistic regression was used to explore associations between patient-level factors and neuroimaging utilization. A Markov model with Monte Carlo simulation was used to estimate neuroimaging utilization over time at the individual patient level.
Results
Migraine diagnoses (OR = 0.6, 95% CI 0.4–0.9) and chronic headaches (routine, chronic OR = 0.3, 95% CI 0.2–0.6; flare-up, chronic OR = 0.5, 95% CI 0.3–0.96) were associated with lower utilization, but even in these populations neuroimaging was ordered frequently. Red flags for intracranial pathology did not increase use of neuroimaging studies (OR = 1.4, 95% CI 0.95–2.2). Neurologist visits (OR = 1.7, 95% CI 0.99–2.9) and first visits to a practice (OR = 3.2, 95% CI 1.4–7.4) were associated with increased imaging. A patient with new migraine headaches has a 39% (95% CI 24–54%) chance of receiving a neuroimaging study after five years and a patient with a flare-up of chronic headaches has a 51% (32–68%) chance.
Conclusions
Neuroimaging is routinely ordered in outpatient headache patients including populations where guidelines specifically recommend against their use (migraines, chronic headaches, no red flags).
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Goulart, A. C., Santos, I. S., Lotufo, P. A., Bensenor, I. M., 2015-10-07 07:57:36 AM
Background
The relationship between cardiovascular risk factors (CVRF) and migraine is controversial and might be different in both genders. These associations were evaluated in Brazilian middle-aged men and women from the Longitudinal Study of Adult Health (ELSA-Brasil).
Methods
The cross-sectional relationship between our main outcome, which was migraine headache (definite, probable and overall), and CVRF was evaluated in the total sample and according to gender. We calculated frequencies and odds ratios (95% CI) for this relationship using binary and multinomial logistic regression analyses in crude, age-adjusted and multivariable models adjusted by potential confounders.
Results
Of 14,953 individuals who completed the data about headache and CVRF, the frequency of one-year migraine was of 29.5% (22.5% in women and 7.0% in men). In the multivariable-adjusted regression analyses, an inverse association between hypertension (OR, 0.53; 95% CI, 0.36–0.79), metabolic syndrome (OR, 0.65; 95% CI, 0.43–0.99) and definite migraine were confirmed for men, but not for women. In the opposite direction, a positive association between migraine headaches (definite, probable and overall) and dyslipidemia (overall migraine OR, 1.25; 95% CI, 1.13–1.38) was observed only for women, but not for men.
Conclusions
A gender influence on the relationship between migraine and CVRF was verified in the ELSA-Brasil.
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Smith, R. M., Robertson, C. E., Garza, I., 2015-10-07 07:57:36 AM
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Lambru, G., Shanahan, P., Matharu, M., 2015-10-07 07:57:36 AM
Background
The management of short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and with short-lasting unilateral neuralgiform headache attacks with autonomic symptoms (SUNA) remains challenging in view of the limited understanding of their pathophysiological mechanisms.
Methods
An initial observation that patients with both chronic migraine (CM) or cluster headache (CH) and SUNCT/SUNA receiving intravenous dihydroergotamine (IV DHE) had complained of dramatic worsening of the latter led to review of the case notes of patients with CM or CH and co-existent SUNCT/SUNA seen between 2008 and 2013 and who had a trial of IV DHE.
Results
Twenty-four patients were identified. IV DHE was ineffective for SUNCT/SUNA in 16 patients, while one patient reported a marginal improvement. Five patients reported dramatic worsening of the SUNCT/SUNA. Moreover, two patients developed new-onset SUNA during their first IV DHE infusion. Out of these seven patients, those requiring repeated courses of IV DHE consistently experienced exacerbations of SUNCT/SUNA which were suppressed with IV lidocaine.
Conclusions
DHE is an ineffective treatment option for SUNCT and SUNA. Physicians who intend to offer IV DHE to CH or CM patients should warn them that IV DHE could exacerbate and possibly even lead to a de novo onset of SUNCT/SUNA. In view of the reported worsening or new onset of SUNCT/SUNA in patients using dopamine agonists for the treatment of pituitary prolactinomas, we speculate that DHE might worsen or induce SUNCT and SUNA, at least in a sub-group of patients, through a perturbation in the dopaminergic system.
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Braunstein, D., Donnet, A., Pradel, V., Sciortino, V., Allaria-Lapierre, V., Lanteri-Minet, M., Micallef, J., 2015-10-07 07:57:36 AM
Introduction
The objective of this study was to estimate and to characterize the actual patterns of triptan use and overuse in France using a drug reimbursement database.
Methods
We included all people covered by the French General Health Insurance System (GHIS) from the Provence-Alpes-Côte-d'Azur (PACA) and Corsica administrative areas who had at least one dispensed dose of triptans between May 2010 and December 2011. All dispensed doses of triptans, migraine prophylactic treatment and psychotropic medications were extracted from the GHIS database. Triptan overuse was defined as triptan use >20 defined daily doses (DDD) per month on a regular basis for more than three consecutive months. Risk of overuse was assessed using logistic regression adjusted for gender and age.
Results
We included 99,540 patients who had at least one prescription of a triptan over the 20 months of the study. Among them, 2243 patients (2.3%) were identified as overusers and received 20.2% of the total DDD prescribed. Twelve percent of overusers and 6.9% of non-overusers were aged more than 65 years (OR: 1.81). Overusers did not have a greater number of prescribers and pharmacists than non-overusers. They were more frequently prescribed a prophylactic medication for migraine treatment (56.8% vs 35.9%, OR: 2.36), benzodiazepines (69.9% vs 54.7%, OR: 1.93) and antidepressants (49.4% vs 30.2%, OR: 2.33).
Conclusions
This work suggests that triptan overuse may be due to insufficient prescriber awareness of appropriate prescribing. The off-label prescription of triptans among the elderly necessitates investigating their cardiovascular risk profile in this sub-group.
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Esserlind, A.-L., Christensen, A. F., Steinberg, S., Grarup, N., Pedersen, O., Hansen, T., Werge, T., Hansen, T. F., Husemoen, L. L. N., Linneberg, A., Budtz-Jorgensen, E., Westergaard, M. L., Stefansson, H., Olesen, J., 2015-10-07 07:57:36 AM
Introduction
The objective of the study was to follow up and to test whether 12 previously identified migraine-associated single nucleotide polymorphisms were associated as risk factors and/or modifying factors for severe migraine traits in a Danish clinic-based population.
Methods
Semi-structured migraine interviews, blood sampling and genotyping were performed on 1806 unrelated migraineurs recruited from the Danish Headache Center. Genotyping was also performed on a control group of 6415 people with no history of migraine. Association analyses were carried out using logistic regression and odds ratios were calculated assuming an additive model for risk. The proxies for severe migraine traits (early onset of migraine; many lifetime attacks, prolonged migraine and tendency to chronification of migraine) were tested against the 12 single nucleotide polymorphisms and a combined genetic score in both a case-control and case-only logistic regression model.
Results
We successfully replicated five out of the 12 previously reported loci and confirmed the same direction of effects for all the 12 single nucleotide polymorphisms. In line with the recently published genome-wide association meta-analysis, the associations were significant for all migraine and migraine without aura but not for migraine with typical aura. Two single nucleotide polymorphisms (rs2274316 and rs11172113) conferred risk of many lifetime attacks inthe case-control analysis. In the case-only analysis, only three single nucleotide polymorphisms showed nominal association with many lifetime attacks and prolonged migraine attacks.
Conclusion
Our study supports previously reported findings on the association of several single nucleotide polymorphisms with migraine. It also suggests that the migraine susceptibility loci may be risk factors for severe migraine traits.
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Park, H.-E., Kim, J.-S., Park, J.-W., Lee, K.-S., 2015-10-07 07:57:36 AM
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Chhetri, S. K., Bindman, D., Joseph, J., Mathur, S., Shaunak, S., 2015-10-07 07:57:36 AM
There is little in the published neurological literature on acephalgic giant cell arteritis (GCA); even less commonly reported are the clinical, radiological and pathological features of GCA presenting with ischaemic stroke and stenosis/occlusion of the basal cerebral arteries. We report a fatal case of GCA manifesting as repeated episodes of cerebral ischaemia with radiological evidence of severe stenosis involving both internal carotid and vertebral arteries and post-mortem histopathological confirmation of GCA.
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Vodonos, A., Novack, V., Zlotnik, Y., Ifergane, G., 2015-10-07 07:57:36 AM
Background
Headache is a common condition, and a common complaint leading patients to emergency departments (ED). There have been a number of studies of the effect of environmental factors on headache, such as weather and air pollutants.
Methods
This retrospective cohort study included data on daily ED visits with a chief complaint of headache in Soroka University Medical Center (SUMC) during 2002–2012. Data on weather and air pollutants were obtained from monitor station in Be'er-Sheva. To estimate the short-term effects of air pollution and temperature on number of daily headache ED visits, we applied generalized linear mixed models (GLMM).
Results
A total of 22,021 ED visits were included in the analysis. An increase in 5℃ in temperature was associated with an increase in ED visits, relative risk (RR) = 1.042, (95% CI 1.009; 1.076). RR for headache was associated with an increase in 10 units of nitrogen dioxide (NO2), RR = 1.110 (95% CI 1.057; 1.167), with a higher effect for older patients.
Discussion
The current findings give evidence of an association between air pollution, weather and ED visits for headache, especially for NO2. Short-term increases in air pollution exposure may trigger headache by increasing pulmonary and systemic inflammation, increasing blood coagulability or altering endothelial function.
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Koehler, P. J., 2015-10-07 07:57:36 AM
Background
Christiaan Huygens (1629–1695) was a Dutch mathematician, physicist, and astronomer. He became well-known as inventor of the pendulum clock and described light as a wave phenomenon. He became Fellow of the Royal Society (London) and member of the Académie des Sciences (Paris). From the correspondence with family members and famous scientists, we learn that he suffered from frequent headaches.
Aim
To study Huygens' 22-volume Oeuvres Complètes (1888–1950) to find letters in which his headaches are mentioned and translate pertinent sections into English.
Conclusions
Although a posthumous diagnosis of Huygens' headaches is somewhat hazardous, the recurrent episodes with incapacitating headache and family history over two generations are suggestive for migraine. It becomes clear that it impeded his writing, reading, and research. From the letters we get an impression of the impact of the headache upon his life and the treatments that were applied in the 17th century.
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Qiu, C., Frederick, I. O., Sorensen, T., Aurora, S. K., Gelaye, B., Enquobahrie, D. A., Williams, M. A., 2015-10-07 07:57:36 AM
Background
Migraine is associated with sleep disturbances in men and non-pregnant women. However, relatively little is known about sleep disturbances among pregnant migraineurs. We investigated sleep disturbances among pregnant women with and without history of migraine.
Methods
This cross-sectional study was conducted among 1324 women who were recruited during early pregnancy. Migraine diagnoses were based on the International Classification of Headache Disorders-II criteria. The Pittsburgh Sleep Quality Index (PSQI) questionnaire was used to evaluate sleep-related characteristics including sleep duration, sleep quality, excessive daytime sleepiness, and other sleep traits. Multivariable logistic regression procedures were used to estimate adjusted odds ratios (AORs) and 95% confidence intervals (CIs).
Results
Migraineurs were more likely than non-migraineurs to report short sleep duration (<6.5 hours) (AOR = 1.47, 95% CI 1.07–2.02), poor sleep quality (PSQI>5) (AOR = 1.73, 95% CI 1.35–2.23), and daytime dysfunction due to sleepiness (AOR = 1.51, 95% CI 1.12–2.02). Migraineurs were also more likely than non-migraineurs to report taking sleep medication during pregnancy (AOR = 1.71, 95% CI 1.20–2.42). Associations were generally similar for migraine with or without aura. The odds of sleep disturbances were particularly elevated among pre-pregnancy overweight migraineurs.
Conclusion
Migraine headache and sleep disturbances are common comorbid conditions among pregnant women.
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de Vries, B., Anttila, V., Freilinger, T., Wessman, M., Kaunisto, M. A., Kallela, M., Artto, V., Vijfhuizen, L. S., Gobel, H., Dichgans, M., Kubisch, C., Ferrari, M. D., Palotie, A., Terwindt, G. M., van den Maagdenberg, A. M., on behalf of the International Headache Genetics Consortium, 2015-10-07 07:57:36 AM
Background
Before the genome-wide association (GWA) era, many hypothesis-driven candidate gene association studies were performed that tested whether DNA variants in genes that had been selected based on prior knowledge about migraine pathophysiology were associated with migraine. Most studies involved small sample sets without robust replication, thereby making the risk of false-positive findings high. Genome-wide marker data of thousands of migraine patients and controls from the International Headache Genetics Consortium provide a unique opportunity to re-evaluate key findings from candidate gene association studies (and other non-GWA genetic studies) in a much larger data set.
Methods
We selected 21 genes from published candidate gene association studies and six additional genes from other non-GWA genetic studies in migraine. Single nucleotide polymorphisms (SNPs) in these genes, as well as in the regions 500 kb up- and downstream, were inspected in IHGC GWAS data from 5175 clinic-based migraine patients with and without aura and 13,972 controls.
Results
None of the SNPs in or near the 27 genes, including the SNPs that were previously found to be associated with migraine, reached the Bonferroni-corrected significance threshold; neither when analyzing all migraine patients together, nor when analyzing the migraine with and without aura patients or males and females separately.
Conclusion
The available migraine GWAS data provide no clear evidence for involvement of the previously reported most promising candidate genes in migraine.
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Maarbjerg, S., Wolfram, F., Gozalov, A., Olesen, J., Bendtsen, L., 2015-10-07 07:57:36 AM
Background
Previous studies demonstrated that a severe neurovascular contact (NVC) causing displacement or atrophy of the trigeminal nerve is highly associated with classical trigeminal neuralgia (TN). There are no studies describing the association between the clinical characteristics of TN and severe NVC.
Methods
Clinical characteristics were prospectively collected from consecutive TN patients using semi-structured interviews in a cross-sectional study design. We evaluated 3.0 Tesla MRI blinded to the symptomatic side.
Results
We included 135 TN patients. Severe NVC was more prevalent in men (75%) compared to women (38%) (p < 0.001), and the odds in favor of severe NVC on the symptomatic side were 5.1 times higher in men compared to women (95% CI 2.3–10.9, p < 0.001). There was no difference between patients with and without severe NVC in age (≥60 years vs. <60) (OR 1.6 95% CI (0.8–3.4), p = 0.199) or duration of disease (p = 0.101).
Conclusions
Severe NVC was much more prevalent in men than in women, who may more often have other disease etiologies causing or contributing to TN. Severe NVC was not associated with age or with duration of disease.
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Greco, R., Bandiera, T., Mangione, A., Demartini, C., Siani, F., Nappi, G., Sandrini, G., Guijarro, A., Armirotti, A., Piomelli, D., Tassorelli, C., 2015-10-07 07:57:36 AM
Background
Systemic nitroglycerin (NTG) activates brain nuclei involved in nociceptive transmission as well as in neuroendocrine and autonomic functions in rats. These changes are considered relevant for migraine because NTG consistently provokes spontaneous-like migraine attacks in migraineurs. Several studies have suggested a relationship between the endocannabinoid levels and pain mediation in migraine. URB937, a peripheral inhibitor of fatty acid amide hydrolase (FAAH)—the enzyme that degrades anandamide, produces analgesia in animal models of pain, but there is no information on its effects in migraine.
Aim
We evaluated whether URB937 alters nociceptive responses in the animal model of migraine based on NTG administration in male rats, using the tail flick test and the plantar and orofacial formalin tests, under baseline conditions and after NTG administration. Furthermore, we investigated whether URB937 affects NTG-induced c-Fos expression in the brain.
Results
During the tail flick test, URB937 showed an antinociceptive effect in baseline conditions and it blocked NTG-induced hyperalgesia. URB937 also proved effective in counteracting NTG-induced hyperalgesia during both the plantar and orofacial formalin tests. Mapping of brain nuclei activated by NTG indicates that URB937 significantly reduces c-Fos expression in the nucleus trigeminalis caudalis and the locus coeruleus.
Conclusions
The data suggest that URB937 is capable of changing, probably via indirect mechanisms, the functional status of central structures that are important for pain transmission in an animal model of migraine.
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Munoz-Islas, E., Gonzalez-Hernandez, A., Lozano-Cuenca, J., Ramirez-Rosas, M. B., Medina-Santillan, R., Centurion, D., MaassenVanDenBrink, A., Villalon, C. M., 2015-10-07 07:57:36 AM
Background
During migraine, capsaicin-sensitive trigeminal sensory nerves release calcitonin gene-related peptide (CGRP), resulting in cranial vasodilatation and central nociception. Moreover, 5-HT is involved in the pathophysiology of migraine and depression. Interestingly, some limited lines of evidence suggest that fluoxetine may be effective in migraine prophylaxis, but the underlying mechanisms are uncertain. Hence, this study investigated the canine external carotid vasodilator responses to capsaicin, α-CGRP and acetylcholine before and after acute and chronic oral treatment with fluoxetine.
Methods
Forty-eight vagosympathectomised male mongrel dogs were prepared to measure blood pressure, heart rate and external carotid blood flow. The thyroid artery was cannulated for infusions of agonists. In 16 of these dogs, a spinal cannula was inserted (C1–C3) for infusions of 5-HT.
Results
The external carotid vasodilator responses to capsaicin, α-CGRP and acetylcholine remained unaffected after intracarotid or i.v. fluoxetine. In contrast, the vasodilator responses to capsaicin, but not those to α-CGRP or acetylcholine, were inhibited after chronic oral treatment with fluoxetine (300 µg/kg; for 90 days) or intrathecal 5-HT.
Conclusions
Chronic oral fluoxetine inhibited capsaicin-induced external carotid vasodilatation, and this inhibition could partly explain its potential prophylactic antimigraine action.
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Wei, X., Yan, J., Tillu, D., Asiedu, M., Weinstein, N., Melemedjian, O., Price, T., Dussor, G., 2015-10-07 07:57:36 AM
Background
Stress is commonly reported to contribute to migraine although mechanisms by which this may occur are not fully known. The purpose of these studies was to examine whether norepinephrine (NE), the primary sympathetic efferent transmitter, acts on processes in the meninges that may contribute to the pain of migraine.
Methods
NE was applied to rat dura using a behavioral model of headache. Primary cultures of rat trigeminal ganglia retrogradely labeled from the dura mater and of rat dural fibroblasts were prepared. Patch-clamp electrophysiology, Western blot, and ELISA were performed to examine the effects of NE. Conditioned media from NE-treated fibroblast cultures was applied to the dura using the behavioral headache model.
Results
Dural injection both of NE and media from NE-stimulated fibroblasts caused cutaneous facial and hindpaw allodynia in awake rats. NE application to cultured dural afferents increased action potential firing in response to current injections. Application of NE to dural fibroblasts increased phosphorylation of ERK and caused the release of interleukin-6 (IL-6).
Conclusions
These data demonstrate that NE can contribute to pro-nociceptive signaling from the meninges via actions on dural afferents and dural fibroblasts. Together, these actions of NE may contribute to the headache phase of migraine.
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Planche, V., Dousset, V., Ouallet, J. C., Tourdias, T., 2015-10-07 07:57:36 AM
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Olesen, J., Ashina, M., 2015-10-07 07:57:36 AM
Introduction
For many years, scientists have debated the possibility that an individual "migraine threshold" determines the likelihood with which individuals may express migraine attacks.
Discussion
Recent discoveries provided evidence for both genetic and environmental influences on individual migraine expression. The question is whether any person may express a migraine attack given a sufficiently strong stimulus or provocation. Here, we reviewed and discussed the ability of nitric oxide to induce migraine-like attacks in normal individuals.
Conclusion
Experimental data show that normal individuals may develop a migraine-like attack and that the human data point to different ways of further developing existing animal and human models.
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Neuroscience
This Week in The Journal
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Reward Processing in the Adolescent Brain: Individual Differences and Relation to Risk Taking
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Induction of Anti-Hebbian LTP in CA1 Stratum Oriens Interneurons: Interactions between Group I Metabotropic Glutamate Receptors and M1 Muscarinic Receptors
An anti-Hebbian form of LTP is observed at excitatory synapses made with some hippocampal interneurons. LTP induction is facilitated when postsynaptic interneurons are hyperpolarized, presumably because Ca2+ entry through Ca2+-permeable glutamate receptors is enhanced. The contribution of modulatory transmitters to anti-Hebbian LTP induction remains to be established. Activation of group I metabotropic receptors (mGluRs) is required for anti-Hebbian LTP induction in interneurons with cell bodies in the CA1 stratum oriens. This region receives a strong cholinergic innervation from the septum, and muscarinic acetylcholine receptors (mAChRs) share some signaling pathways and cooperate with mGluRs in the control of neuronal excitability.
We therefore examined possible interactions between group I mGluRs and mAChRs in anti-Hebbian LTP at synapses which excite oriens interneurons in rat brain slices. We found that blockade of either group I mGluRs or M1 mAChRs prevented the induction of anti-Hebbian LTP by pairing presynaptic activity with postsynaptic hyperpolarization. Blocking either receptor also suppressed long-term effects of activation of the other G-protein coupled receptor on interneuron membrane potential. However, no crossed blockade was detected for mGluR or mAchR effects on interneuron after-burst potentials or on the frequency of miniature EPSPs. Paired recordings between pyramidal neurons and oriens interneurons were obtained to determine whether LTP could be induced without concurrent stimulation of cholinergic axons. Exogenous activation of mAChRs led to LTP, with changes in EPSP amplitude distributions consistent with a presynaptic locus of expression. LTP, however, required noninvasive presynaptic and postsynaptic recordings.
SIGNIFICANCE STATEMENT In the hippocampus, a form of NMDA receptor-independent long-term potentiation (LTP) occurs at excitatory synapses made on some inhibitory neurons. This is preferentially induced when postsynaptic interneurons are hyperpolarized, depends on Ca2+ entry through Ca2+-permeable AMPA receptors, and has been labeled anti-Hebbian LTP. Here we show that this form of LTP also depends on activation of both group I mGluR and M1 mAChRs. We demonstrate that these G-protein coupled receptors (GPCRs) interact, because the blockade of one receptor suppresses long-term effects of activation of the other GPCR on both LTP and interneuron membrane potential. This LTP was also detected in paired recordings, although only when both presynaptic and postsynaptic recordings did not perturb the intracellular medium. Changes in EPSP amplitude distributions in dual recordings were consistent with a presynaptic locus of expression. |
TASK Channels on Basal Forebrain Cholinergic Neurons Modulate Electrocortical Signatures of Arousal by Histamine
Basal forebrain cholinergic neurons are the main source of cortical acetylcholine, and their activation by histamine elicits cortical arousal. TWIK-like acid-sensitive K+ (TASK) channels modulate neuronal excitability and are expressed on basal forebrain cholinergic neurons, but the role of TASK channels in the histamine-basal forebrain cholinergic arousal circuit is unknown. We first expressed TASK channel subunits and histamine Type 1 receptors in HEK cells. Application of histamine in vitro inhibited the acid-sensitive K+ current, indicating a functionally coupled signaling mechanism. We then studied the role of TASK channels in modulating electrocortical activity in vivo using freely behaving wild-type (n = 12) and ChAT-Cre:TASKf/f mice (n = 12), the latter lacking TASK-1/3 channels on cholinergic neurons. TASK channel deletion on cholinergic neurons significantly altered endogenous electroencephalogram oscillations in multiple frequency bands. We then identified the effect of TASK channel deletion during microperfusion of histamine into the basal forebrain. In non-rapid eye movement sleep, TASK channel deletion on cholinergic neurons significantly attenuated the histamine-induced increase in 30–50 Hz activity, consistent with TASK channels contributing to histamine action on basal forebrain cholinergic neurons. In contrast, during active wakefulness, histamine significantly increased 30–50 Hz activity in ChAT-Cre:TASKf/f mice but not wild-type mice, showing that the histamine response depended upon the prevailing cortical arousal state. In summary, we identify TASK channel modulation in response to histamine receptor activation in vitro, as well as a role of TASK channels on cholinergic neurons in modulating endogenous oscillations in the electroencephalogram and the electrocortical response to histamine at the basal forebrain in vivo.
SIGNIFICANCE STATEMENT Attentive states and cognitive function are associated with the generation of EEG activity. Basal forebrain cholinergic neurons are important modulators of cortical arousal and activity, and in this study we investigated the mechanism by which these neurons are activated by the wake-active neurotransmitter histamine. We found that histamine inhibited a class of K+ leak channels called TASK channels and that deletion of TASK channels selectively on cholinergic neurons modulated baseline EEG activity as well as histamine-induced changes in activity. By identifying a discrete brain circuit where TASK channels can influence activity, these results represent new knowledge that enhances our understanding of how subcortical arousal systems may contribute to the generation of attentive states. |
APOE Isoforms Control Pathogenic Subretinal Inflammation in Age-Related Macular Degeneration
Contrary to Alzheimer's disease (AD), the APOE2 allele increases and the APOE4 allele reduces the risk to develop age-related macular degeneration (AMD) compared with the most common APOE3 allele. The underlying mechanism for this association with AMD and the reason for the puzzling difference with AD are unknown. We previously demonstrated that pathogenic subretinal mononuclear phagocytes (MPs) accumulate in Cx3cr1-deficient mice due to the overexpression of APOE, interleukin-6, and CC chemokine ligand 2 (CCL2). We here show using targeted replacement mice expressing the human APOE isoforms (TRE2, TRE3, and TRE4) that MPs of TRE2mice express increased levels of APOE, interleukin-6, and CCL2 and develop subretinal MP accumulation, photoreceptor degeneration, and exaggerated choroidal neovascularization similar to AMD. Pharmacological inhibition of the cytokine induction inhibited the pathogenic subretinal inflammation. In the context of APOE-dependent subretinal inflammation in Cx3cr1GFP/GFP mice, the APOE4 allele led to diminished APOE and CCL2 levels and protectedCx3cr1GFP/GFP mice against harmful subretinal MP accumulation observed in Cx3cr1GFP/GFPTRE3 mice. Our study shows that pathogenic subretinal inflammation is APOE isoform-dependent and provides the rationale for the previously unexplained implication of the APOE2 isoform as a risk factor and the APOE4 isoform as a protective factor in AMD pathogenesis.
SIGNIFICANCE STATEMENT The understanding of how genetic predisposing factors, which play a major role in age-related macular degeneration (AMD), participate in its pathogenesis is an important clue to decipher the pathomechanism and develop efficient therapies. In this study, we used transgenic, targeted replacement mice that carry the three human APOE isoform-defining sequences at the mouse APOE chromosomal location and express the human APOE isoforms. Our study is the first to show how APOE2 provokes and APOE4 inhibits the cardinal AMD features, inflammation, degeneration, and exaggerated neovascularization. Our findings reflect the clinical association of the genetic predisposition that was recently confirmed in a major pooled analysis. They emphasize the role of APOE in inflammation and inflammation in AMD. |
Cortical Low-Frequency Power and Progressive Phase Synchrony Precede Successful Memory Encoding
Neural activity preceding an event can influence subsequent memory formation, yet the precise cortical dynamics underlying this activity and the associated cognitive states remain unknown. We investigate these questions here by examining intracranial EEG recordings as 28 participants with electrodes placed for seizure monitoring participated in a verbal paired-associates memory task. We found that, preceding successfully remembered word pairs, an orientation cue triggered a low-frequency 2–4 Hz phase reset in the right temporoparietal junction with concurrent increases in low-frequency power across cortical regions that included the prefrontal cortex and left temporal lobe. Regions that exhibited a significant increase in 2–4 Hz power were functionally bound together through progressive low-frequency 2–4 Hz phase synchrony. Our data suggest that the interaction between power and phase synchrony reflects the engagement of attentional networks that in large part determine the extent to which memories are successfully encoded.
SIGNIFICANCE STATEMENT Here we investigate the spatiotemporal cortical dynamics that precede successful memory encoding. Using intracranial EEG, we observed significant changes in oscillatory power, intertrial phase consistency, and pairwise phase synchrony that predict successful encoding. Our data suggest that the interaction between power and phase synchrony reflects the engagement of attentional networks that in large part determine the extent to which memories are successfully encoded. |
Maternal Ube3a Loss Disrupts Sleep Homeostasis But Leaves Circadian Rhythmicity Largely Intact
Individuals with Angelman syndrome (AS) suffer sleep disturbances that severely impair quality of life. Whether these disturbances arise from sleep or circadian clock dysfunction is currently unknown. Here, we explored the mechanistic basis for these sleep disorders in a mouse model of Angelman syndrome (Ube3am–/p+ mice). Genetic deletion of the maternal Ube3a allele practically eliminates UBE3A protein from the brain of Ube3am–/p+ mice, because the paternal allele is epigenetically silenced in most neurons. However, we found that UBE3A protein was present in many neurons of the suprachiasmatic nucleus—the site of the mammalian circadian clock—indicating that Ube3a can be expressed from both parental alleles in this brain region in adult mice. We found that while Ube3am–/p+ mice maintained relatively normal circadian rhythms of behavior and light-resetting, these mice exhibited consolidated locomotor activity and skipped the timed rest period (siesta) present in wild-type (Ube3am+/p+) mice. Electroencephalographic analysis revealed that alterations in sleep regulation were responsible for these overt changes in activity. Specifically, Ube3am–/p+ mice have a markedly reduced capacity to accumulate sleep pressure, both during their active period and in response to forced sleep deprivation. Thus, our data indicate that the siesta is governed by sleep pressure, and that Ube3a is an important regulator of sleep homeostasis. These preclinical findings suggest that therapeutic interventions that target mechanisms of sleep homeostasis may improve sleep quality in individuals with AS.
SIGNIFICANCE STATEMENT Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by loss of expression of the maternal copy of the UBE3A gene. Individuals with AS have severe sleep dysfunction that affects their cognition and presents challenges to their caregivers. Unfortunately, current treatment strategies have limited efficacy due to a poor understanding of the mechanisms underlying sleep disruptions in AS. Here we demonstrate that abnormal sleep patterns arise from a deficit in accumulation of sleep drive, uncovering the Ube3a gene as a novel genetic regulator of sleep homeostasis. Our findings encourage a re-evaluation of current treatment strategies for sleep dysfunction in AS, and suggest that interventions that promote increased sleep drive may alleviate sleep disturbances in individuals with AS. |
Multisensory Integration of Visual and Vestibular Signals Improves Heading Discrimination in the Presence of a Moving Object
Humans and animals are fairly accurate in judging their direction of self-motion (i.e., heading) from optic flow when moving through a stationary environment. However, an object moving independently in the world alters the optic flow field and may bias heading perception if the visual system cannot dissociate object motion from self-motion. We investigated whether adding vestibular self-motion signals to optic flow enhances the accuracy of heading judgments in the presence of a moving object. Macaque monkeys were trained to report their heading (leftward or rightward relative to straight-forward) when self-motion was specified by vestibular, visual, or combined visual-vestibular signals, while viewing a display in which an object moved independently in the (virtual) world. The moving object induced significant biases in perceived heading when self-motion was signaled by either visual or vestibular cues alone. However, this bias was greatly reduced when visual and vestibular cues together signaled self-motion. In addition, multisensory heading discrimination thresholds measured in the presence of a moving object were largely consistent with the predictions of an optimal cue integration strategy. These findings demonstrate that multisensory cues facilitate the perceptual dissociation of self-motion and object motion, consistent with computational work that suggests that an appropriate decoding of multisensory visual-vestibular neurons can estimate heading while discounting the effects of object motion.
SIGNIFICANCE STATEMENT Objects that move independently in the world alter the optic flow field and can induce errors in perceiving the direction of self-motion (heading). We show that adding vestibular (inertial) self-motion signals to optic flow almost completely eliminates the errors in perceived heading induced by an independently moving object. Furthermore, this increased accuracy occurs without a substantial loss in the precision. Our results thus demonstrate that vestibular signals play a critical role in dissociating self-motion from object motion. |
Functional Diversity of Subicular Principal Cells during Hippocampal Ripples
Cortical and hippocampal oscillations play a crucial role in the encoding, consolidation, and retrieval of memory. Sharp-wave associated ripples have been shown to be necessary for the consolidation of memory. During consolidation, information is transferred from the hippocampus to the neocortex. One of the structures at the interface between hippocampus and neocortex is the subiculum. It is therefore well suited to mediate the transfer and distribution of information from the hippocampus to other areas. By juxtacellular and whole-cell-recordings in awake mice, we show here that in the subiculum a subset of pyramidal cells is activated, whereas another subset is inhibited during ripples. We demonstrate that these functionally different subgroups are predetermined by their cell subtype. Bursting cells are selectively used to transmit information during ripples, whereas the firing probability in regular firing cells is reduced. With multiple patch-clamp recordings in vitro, we show that the cell subtype-specific differences extend into the local network topology. This is reflected in an asymmetric wiring scheme where bursting cells and regular firing cells are recurrently connected among themselves but connections between subtypes exclusively exist from regular to bursting cells. Furthermore, inhibitory connections are more numerous onto regular firing cells than onto bursting cells. We conclude that the network topology contributes to the observed functional diversity of subicular pyramidal cells during sharp-wave associated ripples.
SIGNIFICANCE STATEMENT Memory consolidation is dependent on hippocampal activity patterns, so called hippocampal ripples. During these fast oscillations, memory traces are transferred from the hippocampus to the neocortex via the subiculum. We investigated the role of single cells in the subiculum during ripples and found that, dependent on their subtype, they are preferentially activated or inhibited. In addition, these two subtypes, the bursting and regular firing type, are differentially integrated into the local network: inhibitory cells are more densely connected to regular firing cells, and communication between regular and bursting cells is unidirectional. Together with earlier findings on different preferential target regions of these subtypes, we conclude that memory traces are guided to target regions of the activated cell type. |
Increased Dosage of High-Affinity Kainate Receptor Gene grik4 Alters Synaptic Transmission and Reproduces Autism Spectrum Disorders Features
The understanding of brain diseases requires the identification of the molecular, synaptic, and cellular disruptions underpinning the behavioral features that define the disease. The importance of genes related to synaptic function in brain disease has been implied in studies describing de novo germline mutations and copy number variants. Indeed, de novo copy number variations (deletion or duplication of a chromosomal region) of synaptic genes have been recently implicated as risk factors for mental retardation or autism. Among these genes is GRIK4, a gene coding for a glutamate receptor subunit of the kainate type. Here we show that mice overexpressinggrik4 in the forebrain displayed social impairment, enhanced anxiety, and depressive states, accompanied by altered synaptic transmission, showing more efficient information transfer through the hippocampal trisynaptic circuit. Together, these data indicate that a single gene variation in the glutamatergic system results in behavioral symptomatology consistent with autism spectrum disorders as well as in alterations in synaptic function in regions involved in social activity. Autistic features of these mice represent powerful tools for improving diagnosis and testing of specific treatments targeting abnormalities in glutamatergic signaling related to autism spectrum disorders.
SIGNIFICANCE STATEMENT A genetic overlap exists between autism spectrum disorders (ASD), currently thought to represent a continuum of the same disorder with varying degrees of severity, and other neurodevelopmental and neuropsychiatric endophenotypes. We show that the duplication of a single gene coding for a high-affinity kainate receptor subunit (i.e., grik4) in a limited area of the brain recapitulates behavioral endophenotypes seen in humans diagnosed with autism (anhedonia, depression, anxiety, and altered social interaction), including some humans with GRIK4 duplications. Therefore, it should be possible to use mice overexpressing grik4 to directly address circuit dysfunctions associated with ASDs and test specific treatments of autism-related behaviors. |
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MODICA is a new iOS app which can be used to securely capture, manage, and share medical photos using your mobile device.
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| Introducing MODICA - a secure, HIPAA-compliant medical camera app and cloud storage service for the iPhone. |
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If you use your mobile device to take photos of patient cases, you should consider a solution designed specifically for medical photography.
MODICA is a new iOS app which can be used to securely capture, manage, and share medical photos using your mobile device. MODICA can help you:
- Keep medical and personal images separate
- Stay compliant with privacy rules using the encrypted cloud backup service
- Obtain and save patient consent directly in the app
- Securely share photos with colleagues
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| MODICA is free and available now from iTunes. |
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Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182,6932607174
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Atlas of Dermatological Diseases of the Nose and Ears,
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Ultrasonography of the Thyroid http://t.co/58dUk76IVq
Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182,6932607174
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Cephalalgia current issue
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Charles, A., 2015-09-30 06:50:43 AM
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Davenport, W. J., 2015-09-30 06:50:43 AM
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Ewering, C., Hasal, N., Alten, F., Clemens, C. R., Eter, N., Oberwahrenbrock, T., Kadas, E. M., Zimmermann, H., Brandt, A. U., Osada, N., Paul, F., Marziniak, M., 2015-09-30 06:50:43 AM
Background
The exact pathophysiology of cluster headache (CH) is still not fully clarified. Various studies confirmed changes in ocular blood flow during CH attacks. Furthermore, vasoconstricting medication influences blood supply to the eye. We investigated the retina of CH patients for structural retinal alterations with optical coherence tomography (OCT), and how these changes correlate to headache characteristics, oxygen use and impaired visual function.
Methods
Spectral domain OCT of 107 CH patients – 67 episodic, 35 chronic, five former chronic sufferers – were compared to OCT from 65 healthy individuals. Visual function tests with Sloan charts and a substantial ophthalmologic examination were engaged.
Results
Reduction of temporal and temporal-inferior retinal nerve fibre layer (RNFL) thickness was found in both eyes for CH patients with a predominant thinning on the headache side in the temporal-inferior area. Chronic CH patients revealed thinning of the macula compared to episodic suffers and healthy individuals. Bilateral thinning of temporal RNFL was also found in users of 100% oxygen compared to non-users and healthy controls. Visual function did not differ between patients and controls.
Discussion
Our OCT findings show a systemic effect causing temporal retinal thinning in both eyes of CH patients possibly due to attack-inherent or medication-induced frequent bilateral vessel diameter changes. The temporal retina with its thinly myelinated parvo-cellular axons and its more susceptible vessels for the vasoconstricting influence of oxygen inhalation seems to be predisposed for tissue damage-causing processes related to CH.
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Dilli, E., Halker, R., Vargas, B., Hentz, J., Radam, T., Rogers, R., Dodick, D., 2015-09-30 06:50:43 AM
Background
Occipital nerve (ON) injections with corticosteroids and/or local anesthetics have been employed for the acute and preventive treatment of migraine for decades. However, to date there is no randomized, placebo-controlled evidence to support the use of occipital nerve block (ONB) for the prevention of migraine.
Objective
The objective of this article is to determine the efficacy of ONB with local anesthetic and corticosteroid for the preventive treatment of migraine.
Participants and methods
Patients between 18 and 75 years old with ICHD-II-defined episodic (> 1 attack per week) or chronic migraine (modified ICHD-II as patients with > 10 days with consumption of acute medications were permitted into the study) were randomized to receive either 2.5 ml 0.5% bupivacaine plus 0.5 ml (20 mg) methylprednisolone over the ipsilateral (unilateral headache) or bilateral (bilateral headache) ON or 2.75 ml normal saline plus 0.25 ml 1% lidocaine without epinephrine (placebo). Patients completed a one-month headache diary prior to and after the double-blind injection. The primary outcome measure was defined as a 50% or greater reduction in the frequency of days with moderate or severe migraine headache in the four-week post-injection compared to the four-week pre-injection baseline period.
Results
Thirty-four patients received active and 35 patients received placebo treatment. Because of missing data, the full analysis of 33 patients in the active and 30 patients in the placebo group was analyzed for efficacy. In the active and placebo groups respectively, the mean frequency of at least moderate (mean 9.8 versus 9.5) and severe (3.6 versus 4.3) migraine days and acute medication days (7.9 versus 10.0) were not substantially different at baseline. The percentage of patients with at least a 50% reduction in the frequency of moderate or severe headache days was 30% for both groups (10/30 vs nine of 30, 0.00, 95% CI –0.22 to 0.23).
Conclusions
Greater ONB does not reduce the frequency of moderate to severe migraine days in patients with episodic or chronic migraine compared to placebo.
The study was registered with ClinicalTrial.gov (NCT00915473).
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Barloese, M., Lund, N., Petersen, A., Rasmussen, M., Jennum, P., Jensen, R., 2015-09-30 06:50:43 AM
Background and aim
Cluster headache (CH) is the headache disorder with the strongest chronobiological traits. The severe attacks of pain occur with diurnal and annual rhythmicity but the precise rhythm and involvement of potential zeitgebers is unknown. Patients complain of poor sleep quality yet this has never been studied. We investigated triggers, rhythms, sleep quality and chronotypes in CH.
Methods
Patients and controls completed questionnaires and structured interviews composed of new and previously validated parts including the Pittsburgh Sleep Quality Index (PSQI) and Morningness-Eveningness Questionnaire (MEQ). Patients were characterized by a CH index, a unified measure of headache burden.
Results
A total of 275 CH patients and 145 matched controls were included. The most common trigger was sleep (80%) and a relationship between clusters and daylight was identified. Of the patients, 82.2% reported diurnal and 56% annual rhythmicity. Patients reported impaired sleep quality (PSQI) (p < 0.0001) and an inverse relationship between time passed since last attack and sleep quality was identified (p < 0.0001). The CH index was positively related to the PSQI (p < 0.0001).
Conclusion
Diurnally, CH exhibits a relationship with night-time and annually with daylight hours. Patients' sleep quality is reduced compared with controls. Results suggest a complex relationship as sleep quality improves between clusters, but remains pathological.
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Vinogradova, L. V., 2015-09-30 06:50:43 AM
Background
Migraine and epilepsy are highly co-morbid neurological disorders associated with episodic dysfunction of both cortical and subcortical networks. The study examined the interrelation between cortical spreading depression, the electrophysiological correlate of migraine aura and seizures triggered at cortical and brainstem levels by repeated sound stimulation in rats with acoustic hypersensitivity (reflex audiogenic epilepsy).
Method
In awake, freely moving rats with innate audiogenic epilepsy, 25 episodes of running seizure (brainstem seizures) were induced by repeated sound stimulation. Spreading depression and seizures were recorded using implanted cortical electrodes.
Results
The first sound-induced brainstem seizures evoked neither spreading depression nor seizures in the cortex. With repetition, brainstem seizures began to be followed by a single cortical spreading depression wave and an epileptiform discharge. Spreading depression was more frequent an early cortical event than seizures: spreading depression appeared after 8.4 ± 1.0 repeated stimulations in 100% rats (n = 24) while cortical seizures were recorded after 12.9 ± 1.2 tests in 46% rats. Brainstem seizure triggered unilateral long-latency spreading depression. Bilateral short-latency cortical spreading depression was recorded only after intense cortical seizures.
Conclusion
These data show that episodic brainstem activation is a potent trigger of unilateral cortical spreading depression. Development of intense seizures in the cortex leads to initiation of spreading depression in multiple cortical sites of both hemispheres.
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Hagen, K., Brenner, E., Linde, M., Gravdahl, G. B., Tronvik, E. A., Engstrom, M., Sonnewald, U., Helde, G., Stovner, L. J., Sand, T., 2015-09-30 06:50:43 AM
Background
Preventive medication is indicated for many migraine patients, but is used in relatively few. The aim of the present study was to evaluate the efficacy of acetyl-l-carnitine as a prophylactic drug in migraine patients.
Methods
A single-center, randomized, triple-blind, placebo-controlled, crossover study was carried out. Men and women, age 18–65 years, with episodic migraine but otherwise healthy, were recruited mostly through advertisements. After a four-week run-in-phase, 72 participants were randomized to receive either placebo or 3 g acetyl-l-carnitine for 12 weeks. After a four-week washout, treatment was switched. The primary outcome was days with moderate or severe headache per four weeks. Secondary outcomes were days with headache, hours with headache, proportion of responders (>50% reduction in migraine days from baseline) and adverse events.
Results
In the complete case analyses, no statistically significant differences were found between acetyl-l-carnitine and placebo in severe or moderate headache days per month (3.0 versus 3.1, p = 0.80), headache days per month (5.1 versus 5.2, p = 0.73) or for the other secondary outcome measures.
Conclusion
In this triple-blind crossover study no differences were found in headache outcomes between acetyl-l-carnitine and placebo. Our results do not provide evidence of benefit for efficacy of acetyl-l-carnitine as prophylactic treatment for migraine.
Trial registration: EUDRACT (2012-001624-36), ClinicalTrials.gov (NCT01695317).
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Woldeamanuel, Y., Rapoport, A., Cowan, R., 2015-09-30 06:50:43 AM
Background and objectives
Headaches recur in up to 87% of migraine patients visiting the emergency department (ED), making ED recidivism a management challenge. We aimed herein to determine the role of corticosteroids in the acute management of migraine in the ED and outpatient care.
Methods
Advanced search strategies employing PubMed/MEDLINE, Web of Science, and Cochrane Library databases inclusive of a relevant gray literature search was employed for Clinical Studies and Systematic Reviews by combining the terms "migraine" and "corticosteroids" spanning all previous years since the production of synthetic corticosteroids ca. 1950 until August 30, 2014. Methods were in accordance with MOOSE guidelines.
Results
Twenty-five studies (n = 3989, median age 37.5 years, interquartile range or IQR 35–41 years; median male:female ratio 1:4.23, IQR 1:2.1–6.14; 52% ED-based, 56% randomized-controlled) and four systematic reviews were included. International Classification of Headache Disorders criteria were applied in 64%. Nineteen studies (76%) indicated observed outcome differences favoring benefits of corticosteroids, while six (24%) studies indicated non-inferior outcomes for corticosteroids. Median absolute risk reduction was 30% (range 6%–48.2%), and 11% (6%–48.6%) for 24-, and 72-hour headache recurrence, respectively. Parenteral dexamethasone was the most commonly (56%) administered steroid, at a median single dose of 10 mg (range 4–24 mg). All meta-analyses revealed efficacy of adjuvant corticosteroids to various abortive medications—indicating generalizability. Adverse effects were tolerable. Higher disability, status migrainosus, incomplete pain relief, and previous history of headache recurrence predicted outcome favorability.
Conclusions
Our literature review suggests that with corticosteroid treatment, recurrent headaches become milder than pretreated headaches and later respond to nonsteroidal therapy. Single-dose intravenous dexamethasone is a reasonable option for managing resistant, severe, or prolonged migraine attacks.
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Bridge, H., Stagg, C. J., Near, J., Lau, C.-i., Zisner, A., Cader, M. Z., 2015-09-30 06:50:43 AM
Background
Visual aura is present in about one-third of migraine patients and triggering by bright or flickering lights is frequently reported.
Method
Using migraine with visual aura patients, we investigated the neurochemical profile of the visual cortex using magnetic resonance spectroscopy. Specifically, glutamate/creatine and GABA/creatine ratios were quantified in the occipital cortex of female migraine patients.
Results
GABA levels in the occipital cortex of migraine patients were lower than that of controls. Glutamate levels in migraine patients, but not controls, correlated with the blood-oxygenation-level-dependent (BOLD) signal in the primary visual cortex during visual stimulation.
Conclusion
Migraine with visual aura appears to disrupt the excitation-inhibition coupling in the occipital cortex.
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Sanchez-Montanez, A., Morana, G., Mancardi, M. M., Janis, S., Severino, M., Verrina, E., Rossi, A., 2015-09-30 06:50:43 AM
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Dilli, E., Dodick, D. W., 2015-09-30 06:50:43 AM
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Charleston, L., 2015-09-30 06:50:43 AM
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2015-09-30 06:50:43 AM
Stefan Seidel, Andreas Böck, Werner Schlegel, Arzu Kilic, Gudrun Wagner, Gloria Gelbmann, Almut Hübenthal, Incifer Kanbur, Sofia Natriashvili, Andreas Karwautz, Christian Wöber and iek Wöber-Bingöl. Increased RLS prevalence in children and adolescents with migraine: A case-control study. Cephalalgia 2012; 32: 693–699. DOI:10.1177/0333102412446207.
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American Journal of Neuroradiology
In Vitro Evaluation of Intra-Aneurysmal, Flow-Diverter-Induced Thrombus Formation: A Feasibility Study [INTERVENTIONAL]
BACKGROUND AND PURPOSE:Intracranial aneurysm treatment by flow diverters aims at triggering intra-aneurysmal thrombosis. By combining in vitro blood experiments with particle imaging velocimetry measurements, we investigated the time-resolved thrombus formation triggered by flow diverters.MATERIALS AND METHODS:Two test setups were built, 1 for particle imaging velocimetry and 1 for blood experiments, both generating the same pulsatile flow and including a silicone aneurysm model. Tests without flow diverters and with 2 different flow-diverter sizes (diameter: 4.5 and 4.0 mm) were performed. In the blood experiments, the intra-aneurysmal flow was monitored by using Doppler sonography. The experiments were stopped at 3 different changes of the spatial extent of the signal.RESULTS:No thrombus was detected in the aneurysm model without the flow diverter. Otherwise, thrombi were observed in all aneurysm models with flow diverters. The thrombi grew from the proximal side of the aneurysm neck with fibrin threads connected to the flow diverter and extending across the aneurysm. The thrombus resulting from the 4.0-mm flow diverter grew along the aneurysm wall as a solid and organized thrombus, which correlates with the slower velocities near the wall detected by particle imaging velocimetry. The thrombus that evolved by using the 4.5-mm flow diverter showed no identifiable growing direction. The entire thrombus presumably resulted from stagnation of blood and correlates with the central vortex detected by particle imaging velocimetry.CONCLUSIONS:We showed the feasibility of in vitro investigation of time-resolved thrombus formation in the presence of flow diverters. |
Cerebral Perfusion Pressure is Maintained in Acute Intracerebral Hemorrhage: A CT Perfusion Study [ADULT BRAIN]
BACKGROUND AND PURPOSE:Although blood pressure reduction has been postulated to result in a fall in cerebral perfusion pressure in patients with intracerebral hemorrhage, the latter is rarely measured. We assessed regional cerebral perfusion pressure in patients with intracerebral hemorrhage by using CT perfusion source data.MATERIALS AND METHODS:Patients with acute primary intracerebral hemorrhage were randomized to target systolic blood pressures of <150 mm Hg (n = 37) or <180 mm Hg (n = 36). Regional maps of cerebral blood flow, cerebral perfusion pressure, and cerebrovascular resistance were generated by using CT perfusion source data, obtained 2 hours after randomization.RESULTS:Perihematoma cerebral blood flow (38.7 ± 11.9 mL/100 g/min) was reduced relative to contralateral regions (44.1 ± 11.1 mL/100 g/min, P = .001), but cerebral perfusion pressure was not (14.4 ± 4.6 minutes–1 versus 14.3 ± 4.8 minutes–1, P = .93). Perihematoma cerebrovascular resistance (0.34 ± 0.11 g/mL) was higher than that in the contralateral region (0.30 ± 0.10 g/mL, P < .001). Ipsilateral and contralateral cerebral perfusion pressure in the external (15.0 ± 4.6 versus 15.6 ± 5.3 minutes–1, P = .15) and internal (15.0 ± 4.8 versus 15.0 ± 4.8 minutes–1, P = .90) borderzone regions were all similar. Borderzone cerebral perfusion pressure was similar to mean global cerebral perfusion pressure (14.7 ± 4.7 minutes–1, P ≥ .29). Perihematoma cerebral perfusion pressure did not differ between blood pressure treatment groups (13.9 ± 5.5 minutes–1 versus 14.8 ± 3.4 minutes–1, P = .38) or vary with mean arterial pressure (r = –0.08, [–0.10, 0.05]).CONCLUSIONS:Perihematoma cerebral perfusion pressure is maintained despite increased cerebrovascular resistance and reduced cerebral blood flow. Aggressive antihypertensive therapy does not affect perihematoma or borderzone cerebral perfusion pressure. Maintenance of cerebral perfusion pressure provides physiologic support for the safety of blood pressure reduction in intracerebral hemorrhage. |
Evaluation for Blunt Cerebrovascular Injury: Review of the Literature and a Cost-Effectiveness Analysis [ADULT BRAIN]
BACKGROUND AND PURPOSE:Evaluation for blunt cerebrovascular injury has generated immense controversy with wide variations in recommendations regarding the need for evaluation and the optimal imaging technique. We review the literature and determine the most cost-effective strategy for evaluating blunt cerebrovascular injury in trauma patients.MATERIALS AND METHODS:A comprehensive literature review was performed with data extracted to create a decision-tree analysis for 5 different strategies: anticoagulation for high-risk (based on the Denver screening criteria) patients, selective DSA or CTA (only high-risk patients), and DSA or CTA for all trauma patients. The economic evaluation was based on a health care payer perspective during a 1-year horizon. Statistical analyses were performed. The cost-effectiveness was compared through 2 main indicators: the incremental cost-effectiveness ratio and net monetary benefit.RESULTS:Selective anticoagulation in high-risk patients was shown to be the most cost-effective strategy, with the lowest cost and greatest effectiveness (an average cost of $21.08 and average quality-adjusted life year of 0.7231). Selective CTA has comparable utility and only a slightly higher cost (an average cost of $48.84 and average quality-adjusted life year of 0.7229). DSA, whether performed selectively or for all patients, was not optimal from both the cost and utility perspectives. Sensitivity analyses demonstrated these results to be robust for a wide range of parameter values.CONCLUSIONS:Selective CTA in high-risk patients is the optimal and cost-effective imaging strategy. It remains the dominant strategy over DSA, even assuming a low CTA sensitivity and irrespective of the proportion of patients at high-risk and the incidence of blunt cerebrovascular injury in high-risk patients. |
FLAIR2: A Combination of FLAIR and T2 for Improved MS Lesion Detection [ADULT BRAIN]
BACKGROUND AND PURPOSE:FLAIR and double inversion recovery are important MR imaging scans for MS. The suppression of signal from CSF in FLAIR and the additional suppression of WM signal in double inversion recovery improve contrast between lesions, WM and GM, albeit at a reduced SNR. However, whether the acquisition of double inversion recovery is necessary is still debated. Here, we present an approach that allows obtaining CSF-suppressed images with improved contrast between lesions, WM and GM without strongly penalizing SNR.MATERIALS AND METHODS:3D T2-weighted and 3D-FLAIR data acquired from September 2014 to April 2015 in healthy volunteers (23.4 ± 2.4 years of age; female/male ratio, 3:2) and patients (44.1 ± 14.0 years of age; female/male ratio, 4:5) with MS were coregistered and multiplied (FLAIR2). SNR and contrast-to-noise measurements were performed for focal lesions and GM and WM. Furthermore, data from 24 subjects with relapsing-remitting and progressive MS were analyzed retrospectively (52.7 ± 8.1 years of age; female/male ratio, 14:10).RESULTS:The GM-WM contrast-to-noise ratio was by 133% higher in FLAIR2 than in FLAIR and improved between lesions and WM by 31%, 93%, and 158% compared with T2, DIR, and FLAIR, respectively. Cortical and juxtacortical lesions were more conspicuous in FLAIR2. Furthermore, the 3D nature of FLAIR2 allowed reliable visualization of callosal and infratentorial lesions.CONCLUSIONS:We present a simple approach for obtaining CSF suppression with an improved contrast-to-noise ratio compared with conventional FLAIR and double inversion recovery without the acquisition of additional data. FLAIR2 can be computed retrospectively if T2 and FLAIR scans are available. |
Diagnostic Impact of Bone-Subtraction CT Angiography for Patients with Acute Subarachnoid Hemorrhage [ADULT BRAIN]
BACKGROUND AND PURPOSE:Detection and evaluation of ruptured aneurysms is critical for choosing an appropriate endovascular or neurosurgical intervention. Our aim was to assess whether bone-subtraction CTA is capable of guiding treatment for cerebral aneurysms in patients with acute SAH and could replace DSA.MATERIALS AND METHODS:We prospectively studied 116 consecutive patients with SAH with 16–detector row bone-subtraction CTA and DSA before intracranial aneurysm treatment. Two independent neuroradiologists reviewed the bone-subtraction CTA blinded to DSA (reference standard). We determined the accuracy of bone-subtraction CTA for aneurysm detection and the measurement of aneurysm dimensions and compared the radiation doses of the 2 imaging modalities.RESULTS:Seventy-one patients (61%) had 74 aneurysms on DSA. Bone-subtraction CTA detected 73 of these aneurysms, but it detected 1 additional aneurysm. On a per-aneurysm basis, sensitivity, specificity, and positive and negative predictive values for bone-subtraction CTA were 99%, 98%, and 99% and 98%, respectively. For aneurysms of ≤3 mm, sensitivity was 94% (95% CI, 73%–99%). Bone-subtraction CTA slightly overestimated neck and dome diameters by <0.2 mm and overestimated the dome-to-neck ratios by 2% on average. Dose-length product was 565 ± 201 mGy x cm for bone-subtraction CTA and 1609 ± 1300 mGy x cm for DSA.CONCLUSIONS:Bone-subtraction CTA is as accurate as DSA in detecting cerebral aneurysms after SAH, provides similar information about aneurysm configuration and measures, and reduces the average effective radiation dose for vascular diagnostics by 65%. Diagnostic equivalence in association with dose reduction suggests replacing DSA with bone-subtraction CTA in the diagnostic work-up of spontaneous SAH. |
Diagnostic Significance of Cortical Superficial Siderosis for Alzheimer Disease in Patients with Cognitive Impairment [ADULT BRAIN]
BACKGROUND AND PURPOSE:Because the diagnostic significance of cortical superficial siderosis for Alzheimer disease and the association between cortical superficial siderosis and the topographic distribution of cerebral microbleeds have been unclear, we investigated the association between cortical superficial siderosis and clinicoradiologic characteristics of patients with cognitive impairment.MATERIALS AND METHODS:We studied 347 patients (217 women, 130 men; mean age, 74 ± 9 years) who visited our memory clinic and underwent MR imaging (3T SWI). We analyzed the association between cortical superficial siderosis and the topographic distribution of cerebral microbleeds plus clinical characteristics including types of dementia. We used multivariate logistic regression analysis to determine the diagnostic significance of cortical superficial siderosis for Alzheimer disease.RESULTS:Twelve patients (3.5%) manifested cortical superficial siderosis. They were older (P = .026) and had strictly lobar cerebral microbleeds significantly more often than did patients without cortical superficial siderosis (50.0% versus 19.4%, P = .02); the occurrence of strictly deep and mixed cerebral microbleeds, however, did not differ in the 2 groups. Alzheimer disease was diagnosed in 162 (46.7%) patients. Of these, 8 patients (4.9%) had cortical superficial siderosis. In the multivariate logistic regression analysis for the diagnosis of Alzheimer disease, lacunar infarcts were negatively and independently associated with Alzheimer disease (P = .007).CONCLUSIONS:Although cortical superficial siderosis was associated with a strictly lobar cerebral microbleed location, it was not independently associated with Alzheimer disease in a memory clinic setting. Additional studies are required to investigate the temporal changes of these cerebral amyloid angiopathy–related MR imaging findings. |
Ultrasound of the Hypoglossal Nerve in the Neck: Visualization and Initial Clinical Experience with Patients [HEAD & NECK]
BACKGROUND AND PURPOSE:The hypoglossal nerve, providing motor innervation for the tongue, can be affected in many diseases of the neck and skull base, leading to dysarthria, dysphagia, and ultimately atrophy of the tongue. We determined the feasibility of direct visualization of the hypoglossal nerve in the neck with ultrasound, testing this technique on healthy volunteers and evaluating it in clinical practice.MATERIALS AND METHODS:The study consisted of 4 parts: first, ultrasound-guided perineural ink injections along the course of the hypoglossal nerve at 24 sides of 12 fresh, nonembalmed cadaver necks. Subsequently, the specimens were dissected to confirm the correct identification of the nerve. The second part was examination of healthy volunteers with ultrasound and measurement of cross-sectional areas for generating reference data. The third part was scanning of healthy volunteers by 2 resident physicians with little and intermediate experience in ultrasound. Fourth was examination with ultrasound of patients with motor symptoms of the tongue.RESULTS:The hypoglossal nerve was correctly identified bilaterally in all cadaveric specimens (24/24) and all volunteers (33/33). The cross-sectional area ranged from 1.9 to 2.1 mm2. The resident physicians were able to locate the nerve in 19 of 22 cases, demonstrating that locating the nerve is reproducible and feasible even with intermediate experience in ultrasound. Finally, alterations of the hypoglossal nerve in disease states could be depicted.CONCLUSIONS:Direct, reliable, and reproducible visualization of the extracranial hypoglossal nerve with ultrasound is feasible. |
Juxtacortical Lesions and Cortical Thinning in Multiple Sclerosis [ADULT BRAIN]
BACKGROUND AND PURPOSE:The role of juxtacortical lesions in brain volume loss in multiple sclerosis has not been fully clarified. The aim of this study was to explore the role of juxtacortical lesions on cortical atrophy and to investigate whether the presence of juxtacortical lesions is related to local cortical thinning in the early stages of MS.MATERIALS AND METHODS:A total of 131 patients with clinically isolated syndrome or with relapsing-remitting MS were scanned on a 3T system. Patients with clinically isolated syndrome were classified into 3 groups based on the presence and topography of brain lesions: no lesions (n = 24), only non–juxtacortical lesions (n = 33), and juxtacortical lesions and non–juxtacortical lesions (n = 34). Patients with relapsing-remitting MS were classified into 2 groups: only non–juxtacortical lesions (n = 10) and with non–juxtacortical lesions and juxtacortical lesions (n = 30). A juxtacortical lesion probability map was generated, and cortical thickness was measured by using FreeSurfer.RESULTS:Juxtacortical lesion volume in relapsing-remitting MS was double that of patients with clinically isolated syndrome. The insula showed the highest density of juxtacortical lesions, followed by the temporal, parietal, frontal, and occipital lobes. Patients with relapsing-remitting MS with juxtacortical lesions showed significantly thinner cortices overall and in the parietal and temporal lobes compared with those with clinically isolated syndrome with normal brain MR imaging. The volume of subcortical structures (thalamus, pallidum, putamen, and accumbens) was significantly decreased in relapsing-remitting MS with juxtacortical lesions compared with clinically isolated syndrome with normal brain MR imaging. The spatial distribution of juxtacortical lesions was not found to overlap with areas of cortical thinning.CONCLUSIONS:Cortical thinning and subcortical gray matter volume loss in patients with a clinically isolated syndrome or relapsing-remitting MS was related to the presence of juxtacortical lesions, though the cortical areas with the most marked thinning did not correspond to those with the largest number of juxtacortical lesions. |
Differentiating Tumor Progression from Pseudoprogression in Patients with Glioblastomas Using Diffusion Tensor Imaging and Dynamic Susceptibility Contrast MRI [FUNCTIONAL]
BACKGROUND AND PURPOSE:Early assessment of treatment response is critical in patients with glioblastomas. A combination of DTI and DSC perfusion imaging parameters was evaluated to distinguish glioblastomas with true progression from mixed response and pseudoprogression.MATERIALS AND METHODS:Forty-one patients with glioblastomas exhibiting enhancing lesions within 6 months after completion of chemoradiation therapy were retrospectively studied. All patients underwent surgery after MR imaging and were histologically classified as having true progression (>75% tumor), mixed response (25%–75% tumor), or pseudoprogression (<25% tumor). Mean diffusivity, fractional anisotropy, linear anisotropy coefficient, planar anisotropy coefficient, spheric anisotropy coefficient, and maximum relative cerebral blood volume values were measured from the enhancing tissue. A multivariate logistic regression analysis was used to determine the best model for classification of true progression from mixed response or pseudoprogression.RESULTS:Significantly elevated maximum relative cerebral blood volume, fractional anisotropy, linear anisotropy coefficient, and planar anisotropy coefficient and decreased spheric anisotropy coefficient were observed in true progression compared with pseudoprogression (P < .05). There were also significant differences in maximum relative cerebral blood volume, fractional anisotropy, planar anisotropy coefficient, and spheric anisotropy coefficient measurements between mixed response and true progression groups. The best model to distinguish true progression from non–true progression (pseudoprogression and mixed) consisted of fractional anisotropy, linear anisotropy coefficient, and maximum relative cerebral blood volume, resulting in an area under the curve of 0.905. This model also differentiated true progression from mixed response with an area under the curve of 0.901. A combination of fractional anisotropy and maximum relative cerebral blood volume differentiated pseudoprogression from nonpseudoprogression (true progression and mixed) with an area under the curve of 0.807.CONCLUSIONS:DTI and DSC perfusion imaging can improve accuracy in assessing treatment response and may aid in individualized treatment of patients with glioblastomas. |
Endolymphatic Hydrops Reversal following Acetazolamide Therapy: Demonstration with Delayed Intravenous Contrast-Enhanced 3D-FLAIR MRI [HEAD & NECK]
SUMMARY:Endolymphatic hydrops, the primary pathologic alteration in Menière disease, can be visualized by using delayed intravenous contrast-enhanced 3D-FLAIR MR imaging. It is not known whether MR imaging–demonstrable changes of hydrops fluctuate with disease activity or are fixed. We describe the results of baseline and posttreatment MR imaging studies in a group of subjects with Menière disease with hydrops who were treated with acetazolamide. Seven subjects with untreated Menière disease with MR imaging evidence of hydrops had repeat MR imaging during acetazolamide treatment. Symptoms and imaging findings were assessed at each time point. Five subjects showed symptom improvement, of whom 3 had improvement or resolution of hydrops. One subject had recurrent symptoms with recurrent hydrops after discontinuing therapy. Two had unchanged hydrops despite symptom improvement. Subjects with unchanged symptoms had unchanged hydrops. Hydrops reversal may be seen with acetazolamide treatment in Menière disease. MR imaging may provide an additional biomarker of disease.
Standardized Brain Tumor Imaging Protocol for Clinical Trials [letter]
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ERRATUM [correction]
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[research-article]
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We Are Not Alone [editorial]
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Intracranial Aneurysms: Wall Motion Analysis for Prediction of Rupture [INTERVENTIONAL]
SUMMARY:Intracranial aneurysms are a common pathologic condition with a potential severe complication: rupture. Effective treatment options exist, neurosurgical clipping and endovascular techniques, but guidelines for treatment are unclear and focus mainly on patient age, aneurysm size, and localization. New criteria to define the risk of rupture are needed to refine these guidelines. One potential candidate is aneurysm wall motion, known to be associated with rupture but difficult to detect and quantify. We review what is known about the association between aneurysm wall motion and rupture, which structural changes may explain wall motion patterns, and available imaging techniques able to analyze wall motion. |
Hot Topics in Research: Preventive Neuroradiology in Brain Aging and Cognitive Decline [ADULT BRAIN]
SUMMARY:Preventive neuroradiology is a new concept supported by growing literature. The main rationale of preventive neuroradiology is the application of multimodal brain imaging toward early and subclinical detection of brain disease and subsequent preventive actions through identification of modifiable risk factors. An insightful example of this is in the area of age-related cognitive decline, mild cognitive impairment, and dementia with potentially modifiable risk factors such as obesity, diet, sleep, hypertension, diabetes, depression, supplementation, smoking, and physical activity. In studying this link between lifestyle and cognitive decline, brain imaging markers may be instrumental as quantitative measures or even indicators of early disease. The purpose of this article is to provide an overview of the major studies reflecting how lifestyle factors affect the brain and cognition aging. In this hot topics review, we will specifically focus on obesity and physical activity. |
Subspecialty Virtual Impact Factors within a Dedicated Neuroimaging Journal [EDITORIAL PERSPECTIVES]
BACKGROUND AND PURPOSE:The growing number of subspecialties within neuroradiology compete for pages in neuroradiology journals. We performed a bibliometric analysis of the American Journal of Neuroradiology to identify the virtual Impact Factor of different journal subsections and article topics.MATERIALS AND METHODS:Original Research and Review Articles published in American Journal of Neuroradiology during 2010–2012 were evaluated. The journal section for each article was recorded, and the number of citations was evaluated by using the Web of Science database. Numbers of citations within the first 2 years after publication were evaluated, normalized to the 2013 journal Impact Factor (for American Journal of Neuroradiology, 3.675), and used to calculate a virtual Impact Factor for different journal subsections.RESULTS:One thousand forty-nine Original Research and Review Articles were published during this time, which obtained an average of 6.59 citations each within their first 2 years after publication; 91.8% of articles obtained at least 1 citation. Expedited Publications had the greatest number of citations, averaging 43.7 citations each (virtual Impact Factor, 24.39), followed by Review Articles averaging 9.39 citations each (virtual Impact Factor 5.23). Virtual Impact Factors for other sections were the following: Interventional, 4.54; Brain, 3.70; Pediatrics, 2.91; Functional, 2.74; Head & Neck, 2.24; and Spine, 1.86. Virtual Impact Factors for article topics were the following: interventional, 4.75; functional/advanced, 3.79; brain, 3.66; pediatrics, 2.99; head and neck, 2.46; and spine, 2.32.CONCLUSIONS:Citation patterns of Original Research and Review Articles in American Journal of Neuroradiology varied widely on the basis of subsections. Understanding the citation patterns of specific topics and subsections of a journal may aid authors and editors in evaluating the appropriate balance among various topics and allow authors to determine whether their articles are being cited at a level expected for similar ones in a journal. |
Social Media in Medical Education [SOCIAL MEDIA VIGNETTE]
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Accuracy of Parenchymal Cerebral Blood Flow Measurements Using Pseudocontinuous Arterial Spin-Labeling in Healthy Volunteers [ADULT BRAIN]
BACKGROUND AND PURPOSE:The arterial spin-labeling method for CBF assessment is widely available, but its accuracy is not fully established. We investigated the accuracy of a whole-brain arterial spin-labeling technique for assessing the mean parenchymal CBF and the effect of aging in healthy volunteers. Phase-contrast MR imaging was used as the reference method.MATERIALS AND METHODS:Ninety-two healthy volunteers were included: 49 young (age range, 20–30 years) and 43 elderly (age range, 65–80 years). Arterial spin-labeling parenchymal CBF values were averaged over the whole brain to quantify the mean pCBFASL value. Total CBF was assessed with phase-contrast MR imaging as the sum of flows in the internal carotid and vertebral arteries, and subsequent division by brain volume returned the pCBFPCMRI value. Accuracy was considered as good as that of the reference method if the systematic difference was less than 5 mL/min/100 g of brain tissue and if the 95% confidence intervals were equal to or better than ±10 mL/min/100 g.RESULTS:pCBFASL correlated to pCBFPCMRI (r = 0.73; P < .001). Significant differences were observed between the pCBFASL and pCBFPCMRI values in the young (P = .001) and the elderly (P < .001) volunteers. The systematic differences (mean ± 2 standard deviations) were –4 ± 14 mL/min/100 g in the young subjects and 6 ± 12 mL/min/100 g in the elderly subjects. Young subjects showed higher values than the elderly subjects for pCBFPCMRI (young, 57 ± 8 mL/min/100 g; elderly, 54 ± 7 mL/min/100 g; P = .05) and pCBFASL (young, 61 ± 10 mL/min/100 g; elderly, 48 ± 10 mL/min/100 g; P < .001).CONCLUSIONS:The limits of agreement were too wide for the arterial spin-labeling method to be considered satisfactorily accurate, whereas the systematic overestimation in the young subjects and underestimation in the elderly subjects were close to acceptable. The age-related decrease in parenchymal CBF was augmented in arterial spin-labeling compared with phase-contrast MR imaging. |
Gray Matter Volume Reduction Is Associated with Cognitive Impairment in Neuromyelitis Optica [ADULT BRAIN]
BACKGROUND AND PURPOSE:Whether gray matter impairment occurs in neuromyelitis optica is a matter of ongoing debate, and the association of gray matter impairment with cognitive deficits remains largely unknown. The purpose of this study was to investigate gray matter volume reductions and their association with cognitive decline in patients with neuromyelitis optica.MATERIALS AND METHODS:This study included 50 patients with neuromyelitis optica and 50 sex-, age-, handedness-, and education-matched healthy subjects who underwent high-resolution structural MR imaging examinations and a battery of cognitive assessments. Gray matter volume and cognitive differences were compared between the 2 groups. The correlations of the regional gray matter volume with cognitive scores and clinical variables were explored in the patients with neuromyelitis optica.RESULTS:Compared with healthy controls (635.9 ± 51.18 mL), patients with neuromyelitis optica (602.8 ± 51.03 mL) had a 5.21% decrease in the mean gray matter volume of the whole brain (P < .001). The significant gray matter volume reduction in neuromyelitis optica affected the frontal and temporal cortices and the right thalamus (false discovery rate correction, P < .05). The regional gray matter volumes in the frontal and temporal cortices were negatively correlated with disease severity in patients with neuromyelitis optica (Alphasim correction, P < .05). Patients with neuromyelitis optica had impairments in memory, information processing speed, and verbal fluency (P < .05), which were correlated with gray matter volume reductions in the medial prefrontal cortex and thalamus (Alphasim correction, P < .05).CONCLUSIONS:Gray matter volume reduction is present in patients with neuromyelitis optica and is associated with cognitive impairment and disease severity in this group. |
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Rare Diseases
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OrphaNews : the newsletter of the Rare Disease Community
Editorial
RD-ACTION: the new European Rare Disease Joint Action
RD-ACTION, the new Joint Action consisting of the member states of the European Union for rare diseases, was launched on 17 September in Luxembourg, under the auspices of John Ryan, Acting Director of the Health Division and Food Security (DG Health), Jacques Remacle, Head of Health CHAFEA unit (Consumers, Health, Agriculture and Food Executive Agency) and Patrice Dosquet, representing the French Ministry of Health.
Following the two previous Joint Actions - Orphanet Joint Action and EUCERD - RD-ACTION represents renewed support of the European Commission (EC) to rare diseases, through its Directorate General for Health (DG SANTE). RD-ACTION has three main objectives:
- to contribute to the implementation, by member states, the recommendations of the EC Panel in relation to policies on these diseases,
- support the development of Orphanet and make it sustainable, and finally
- help Member States to introduce the ORPHA code in their health systems to make rare diseases visible.
With a global budget of €8,344,079, this work will last three years (until June 2018), following the logic of coherence and continuity vis-à-vis the previous actions, but aims to go further in terms of concrete implementation and consolidation policies.
This action is coordinated by Orphanet (INSERM), bringing together no less than 63 European and non-European participants. The responsibility of implementing the various actions will be carried out by Orphanet (Ana Rath), University of Newcastle (Kate Bushby, coordinator of the EUCERD Joint Action which just ended), the German Institute for Documentation and Medical Information DIMDI (Stefanie Weber), the University of Vienna (Till Voigtländer) and EURORDIS (Yann LeCam). The National Bank of Rare Diseases Data ( BNDMR) represented by Rémy Choquet, will work towards the codification, notably the requirement of definition and bringing solutions to the Member States for the implementation of coding rare diseases. DIMDI and the Register of the Venetian region (Paola Facchin) will drive the implementation and testing of these solutions. EURORDIS will work towards dissemination actions along with Orphanet and Higher Health Institute ( ISS, Italy). The dissemination actions include the 8th European Conference on Rare Diseases and Orphan Products, 26-28 May 2016, Edinburgh. The Directorate General of Health (DGS France, represented by Patrice Dosquet) will lead the work towards a financially sustainable European Orphanet database.
RD-ACTION was designed in the spirit of integration and coherence between the data produced by Orphanet, which provides, among others, the necessary analysis towards policy recommendations, and political action that will then guide the production, operation and dissemination of this data. Participants will ensure effective communication between the reality of each state and the EC Panel, in order to concretely support the implementation of their recommendations.
Read the European Commission press release on RD ACTION
Spotlight on...
Working for rare diseases: EUCERD Joint Action draws to a close and looks to the future
On 15 September, over 50 participants from across Europe attended the Final Conference of the EUCERD Joint Action. This event was organised to show case the achievements of the Joint Action, which ran from March 2012 to November 2015, and to analyse the current state of the art of rare disease activity across the European Union, by exploring progress and remaining challenges in key areas such as healthcare, social care and research. The even was a good opportunity to strenghten collaborations with the stakeholders present and relevant initiatives in the field, and to provided the apt moment to hand over the activities led by the Joint Action to the next Joint Action on rare diseases, RD-Action (see Editorial).
The outcomes of the EUCERD Joint Action, in particular the resources and recommendations elaborated in collaboration with the European Union Committee of Experts on Rare Diseases and EC Expert Group on Rare Diseases, were presented in the morning session. Participants heard about topics as diverse as quality of care and centres of expertise, RD European Reference Networks, social services for RD, cross-border genetic testing and the codification of rare diseases. The work lead in the context of the Joint Action in support to the EUCERD and Commission Expert Group on Rare Diseases has led to the adoption of 5 recommendations in the past three years, with two other recommendations, on genetic testing and social care under discussion currently. In terms of important resources for the community, the Joint Action also supported the elaboration of the annual report on the State of the Art of Rare Diseases Activities in Europe, a 'go-to' source of information on activities in the field of at national and European level aimed at promoting the exchange of information and monitoring the implementation of rare disease policy: this report will continue to be produced in a more dynamic format in the future RD-Action (see Editorial).
The presentations of the activities of the Joint Action were followed by three sessions dedicated to priority areas in the field of rare diseases, informing participants about the latest outcomes of a number of European projects in each area and the efforts made by the EUCERD Joint Action to explore synergies and to link this work into the discussions at the level of the EC Expert Group on Rare Diseases.
The first of these sessions was dedicated to Rare Disease Research, Therapeutics and Translation into the Sphere of Health, with presentations from the Rare Best-Practices project, Burqol-RD, a project aimed at exploring the impact of health policies, interventions and treatments in the field of rare diseases, the transnational research support mechanism E-Rare, and the International Rare Disease Research Consortium concerning the impact of IRDiRC policies at national level. The main issued discussed during this session was that of sustainability of the resources produced via these initiatives, and the importance in particular of research into health economics, as regards rare diseases, to inform the implementation of rare disease policies at national level.
The following session explored the integration of the results of a number of initiatives concerning rare disease registries, a field where the EU has invested resources through a multitude of projects (such as EPIRARE, the EUCERD Joint Action, and the PARENT Joint Action) with a view to developing an appropriate model for a European Platform for Rare Disease Registration. This platform, recently created at the EC's Joint Research Centre in Ispra, Italy, has to date taken over the responsibilities for the management of the central support of the Eurocat congenital anomalies registry, and the European Surveillance of Cerebal Palsy registry. Stakeholders in the field of rare diseases are still waiting from the JRC confirmation of the governance structure, road map and list of services to be provided by the Platform. In particular, Member States who are in the process of creating national rare disease registration systems, or who are considering this direction, are looking for confirmation of the possible support that will be provided, and the guidelines for interoperability (such as a minimum data set) which could be expected.
The final session was dedicated to national plans and strategies for rare diseases, in particular support to the implementation of national activities in this area. The EUCERD Joint Action, continuing the activities of the Europlan project (2008-2011) supported the organisation of over 20 national conferences and debrief sessions across Europe with the close collaboration of national patient alliances and organisations, to ensure the tranmission of European recommendations at national level and appropriate support to Member States in the elaboration and/or implementation of their initiatives. To date, nearly all European Member States have adopted a plan/strategy for rare diseases, with those not yet having adopted a plan in the final stages of elaboration. The next challenge will be the implementation of these plans/strategies, for which very few have a dedicated budget and for some of which need to be translated into concrete actions. The EUCERD Joint Action, through the national conferences and an analysis of these plans, has been able to extract a number of good practices that could help Member States in the implementation of their plans, which will be available shortly.
The day finished by establishing the list of possible priorities in the rare disease policy field to be explored by the Expert Group on Rare Diseases with the support of the new RD-Action for rare diseases (see Editorial). The Commission and the Coordinator of the EUCERD Joint Action, Kate Bushby, thanked the partners and the many participants in the conferences and workshops organised over the past 3 years, for their hard work and wished them success in the future work of the next Joint Action.
The report of the conference will soon be available online.
EU Policy News
EMA
Submit expressions of interest to represent civil society at the EMA
The Health and Food Safety Directorate-General of the European Commission has extended the deadline for its calls for expressions of interest to represent civil society in two scientific committees of the European Medicines Agency (EMA): the Pharmacovigilance Risk Assessment Committee (PRAC) and the Committee for Advanced Therapies (CAT). For both calls, expressions of interest should be submitted to the European Commission no later than 18 October 2015, either by email or post. Further information on the assessment criteria and the application process can be found on the Commission's website.
Call for civil society members to join two EMA committees
National & International Policy Developments
Comprehensive policy for patients with rare diseases in Philippines
The House of Representatives in Philippines recently approved a comprehensive policy on services for patients with rare diseases that will provide them with timely and adequate access to healthcare, information, and products to treat their conditions. This will be done primarily through the establishment of a comprehensive and sustainable health system for identification, referral, and management of patients with rare diseases—integrated within the current public health system; and the inclusion of rare disease benefit package in PhilHealth.
The bill stipulates giving regulatory and fiscal incentives to support research and development activities on rare diseases and manufacturing of affordable drugs or products. Likewise, the bill provides for the design and maintenance of a rare disease registry containing data on cases, patients, drugs and products for rare diseases. Data from the registry will be used in policy formulation. The provisions in the bill are set to address the current challenges being faced by patients afflicted with rare diseases, their families and caregivers, and their healthcare providers.
This bill defines a rare disease as one that affects 1/20,000 in the Philippines. It provides a preliminary list of rare diseases and the provision of inclusion of others under the advisement of the National Institute of Health in the United States.
Read the report on this topic by National Academy of Science and Technology, Philippines
Other European news
The rare disease persons card implementation in Portugal
The Portuguese Ministry of Health Shared Services and Directorate General of Health, recently announced the implementation of the Rare Disease Person's Card (RDPC). Coded using the ORPHA code system, this card is meant to identify the rare disease patient and display the relevant information of the condition as well as information especially required during an emergency situation. An article published in Procedia Computer Science describes the process of preparation, approval and the regulatory model of the card. According to the authors, due to nascent stage of the implementation of these cards, there is still room for the card to evolve and expand. Still, 828 cards have been requested through the family physician of the concerned patients, regarding 738 different rare diseases, half of which have been activated. The card is increasing awareness and empowerment of rare disease's patients, pushing the project forward and improving health care.
Download the document from Direcção-Geral da Saúde
Read the open access article
Sample of the adult British population want genetic testing of children for adult-onset conditions
Almost all the guidelines published till date on genetic testing on children for adult onset conditions recommend deferring such tests unless there is a clear indication that it will prevent the future outcome of the condition. Whether the general public agrees with this recommendation is addressed in an article published in European Journal of Human Genetics.
Testing the attitudes of a representative sample of the adult-British public revealed that, contrary to the guidance documents, 47% believed that parents should be able to test their child for adult-onset conditions, even if there is no treatment or prevention at time of testing. Younger respondents of the survey and men were more likely to support this kind of testing as well as carrier testing. The authors also presented 4 arguments in support of deferring testing to the participants, out of which "a child's future ability to decide for her/himself if and when to be tested" was generally the least supported argument in the sample. However, the authors noted that women were significantly more likely to consider all 4 arguments as valid to defer testing for adult onset conditions.
Read the Open Access article
Sample of Danish population want disclosure of incidental findings from NGS studies
Another article has studied an equally contentious issue –disclosure of incidental findings - is published in European Journal of Human Genetics. Here the authors also find that contrary to the recommendations of professional organisations, participants in next generation studies wanted disclosure of all incidental findings. The authors investigated if participants recruited from the Region of Southern Denmark want disclosure of incidental findings and which ones would they want to know more about. According to the authors most participants wanted disclosure of all incidental findings; only 3% did not want any disclosure, while 36% wanted disclosure only on actionable variants. According to the authors due to the disparity of opinion between the official recommendation and the sample studies "options for reporting IFs in research studies (could) be incorporated in the consent form."
Consult the Pubmed abstract
Other International News
Discussion paper by the Australian government to support people with chronic and complex health conditions
To better support people with chronic and complex health conditions, the Australian Government has released a discussion paper by the Primary Health Care Advisory Group, to examine options for health reform and provide a report to the Australian Government in late 2015. The paper is designed to set out the case for change and introduce some possible options to improve primary health care for people with chronic and complex conditions. In order to engage all stakeholders, consultation will be held with the Advisory Group. Results of the survey that accompanied the discussion paper will be out shortly.
Read more on Therapeutic Goods Administration, Australia
Contradictions of public health policies geared to rare disorders in Brazil
A paper published in Portuguese presents information of the rare disease health policy in Brazil, using the example of Ostegenesis Imperfecta. The paper details the contradictions, especially with respect to therapeutic decisions and the strengthening of the specialized network for addressing this condition which are expressed in the drafting and final text of the new law.
Consult the Pubmed abstract
Sickle cell disease among children in Africa
An article published in International Journal of Africa Nursing Sciences provides an integrative review of 63 references related sickle cell disease among children in Africa, focussing on the incidence, prevalence, morbidity, and mortality; current practices and challenges related to screening, diagnosis, and treatment. From this data the authors also provide recommendations for practice, policy, and research to improve health outcomes of children with sickle cell disease in Africa.
Read the Open Access article
Guidance Documents and Recommendations
22q11.2 deletion syndrome: guidelines for the management
Consult the Pubmed abstract
To read more about " 22q11.2 deletion syndrome"
Genet Med. ; 17(8):599-609 ; August 2015
Cushing syndrome: guidelines on treatment
Consult the Pubmed abstract
To read more about " Cushing syndrome"
J Clin Endocrinol Metab. ; 100(8):2807-31 ; August 2015
Congenital hypogonadotropic hypogonadism: European consensus statement on diagnosis and treatment
Consult the Pubmed abstract
To read more about " Congenital hypogonadotropic hypogonadism"
Nat Rev Endocrinol. ; 11(9):547-64 ; September 2015
Pemphigus vulgaris/foliaceus and bullous pemphigoid: guidelines for the treatment
Consult the Pubmed abstract
To read more about " Pemphigus vulgaris"
To read more about " Pemphigus foliaceus"
To read more about " Bullous pemphigoid"
J Dtsch Dermatol Ges.
Facioscapulohumeral dystrophy: guidelines on evaluation, diagnosis and management
Consult the Pubmed abstract
To read more about " Facioscapulohumeral dystrophy"
Neurology ; 85(4):357-64 ; July 2015
Bioinformatics, Registries and Data Management
How do paediatric biobanks look at various aspects of obtaining consent from the paediatric population
Guidelines such as Code of Federal Regulations and WMA Declaration of Helsinki recommend expressed consent from the paediatric population before inclusion of their health data in biobanks. This issue has brought forth many ethical concerns especially with regards to the child's role in these procedures which is discussed in an article published in European Journal of Human Genetics. The authors of this article provide the results of an international multiple-case study which included four biobanks addressing diverse health concerns with the collection of a variety of data from the paediatric population.
They addressed "four themes linked to the child's role in the consent procedure emerged from the multiple-case study: (1) motives to involve the child, (2) informing the child, (3) the role of dissent, assent and consent and (4) voluntariness of children to participate." This study recognises the motives to involve consent of the child where respect for the child as an intrinsic motive to involve children while adherence to regulation was recognised by all as important. The authors also detail how personal verbal information is utilised for informing the child even though it is not mentioned in the regulation. While the authors say that assent and consent differs between biobanks, the question of how respecting dissent - is followed by the biobanks is unclear. The authors also show that although children agree to participate in biobanks to different reasons, coercion from parents may be the overarching one.
The authors believe that these "insight(s) (are) valuable when designing paediatric biobank governance."
Read the Open Access article
Long tail economics and rare disease research: the impact of next generation sequencing for rare mendelian disorders
An article published in Genetics Research discusses how next generation sequencing (NGS) based research on rare diseases has come a long way and the effect of long tail economics on rare diseases research. Long tail statistics has been commonly used to understand the rise of internet retailers, crowdfunding, crowdsourcing etc., where a large share of the data rests within its tail unlike a normal distribution. The authors believe that the trend observed in rare disease research, especially in terms of the developments in NGS, can benefit from the two themes derived from long tailed economics - increased access and reduced cost.
In this context, increased access would mean that the researcher would be able to look through a sea of data produced thanks to whole genome and whole exome sequencing and find what they are looking for (gene, disease, phenotype) . They also detail the developments in bioinformatics that has led to the development of this enormous amount of data which in turn required better curative and sharing efforts. The authors refer reduced cost to the reduction of overhead costs by centralising resources where the curative and sharing efforts come in play. They also address the issue of reimbursement that comes with the rising cost of sequencing. According to the authors "as a long-tailed problem, continued discovery of rare diseases requires a funding infrastructure that can sustainably support the work needed to identify the great number of rare diseases", for which they believe a good source is crowdfunding. The authors believe that "the principles derived from long-tail economics shape our understanding of the recent development of this field and offer insight towards needed improvements."
The authors of this article belong to the Rare Genomics Institute that has recently launched 10 crowdfunding campaigns to sequence exomes of rare disease patients.
Read the PubMed abstract
Screening and Testing
Regulating laboratory developed tests in the United States: the current controversy
A perspective published by stakeholders in Genetic Testing and Molecular Biomarkerscomments on the current legislation mandating the United States Food and Drug Administration as the regulatory body overseeing Laboratory Developed Tests (LDTs).
The authors explain that historically LDTs are subject to regulation by the Clinical Laboratory Improvement Amendments (CLIA) of Centers for Medicare and Medicaid Services (CMS). However, in 2015, the FDA announced the establishment of the FDA/CMS Task Force on LDT Quality Requirements to oversee changes to the LDT regulatory landscape. The FDA described a premarket review process that would require confirmation of the analytical and clinical validity of new LDTs before the lab is permitted to administer those tests. Following this announcement a debate has ensued in the context of the 21st Century Cures Act with valid arguments from supporters and detractors due to which the Congress has requested for feedback. However, the resulting whitepaper did not contain specific information directly addressing this issue. The authors express concern that stakeholders are still speculating about the trajectory of LDT regulation.
Access the review
Article reviewing the limits of FDA's authority to regulate laboratory developed diagnostic tests
A related article published in the Food and Drug Law Journal addresses FDA's current mandate to regulate laboratory developed diagnostic tests. The author believes that this oversight could prove to be intrusive and has the potential to slow the progress of genomic discovery, interfere with scientific inquiry and suppress investigators' and clinicians' rights to freedom of speech and prove to be federalist in action (U.S wants states to mandate practise of medicine). According to the author this article is written with the goal to help genomics researchers understand how FDA's research regulations may apply to research that uses high-throughput DNA sequencing.
Read the Open Access article
Newborn screening in Australia: current environment and future perspectives
The current state of newborn bloodspot screening in Australia and the lessons it needs to learn from international programmes to upgrade its operation is explained in Frontiers in Public Health. The authors say that NBS has been operating successfully in Australia for almost 50 years but currently it does not have any coherent national policy or decision-making process that is concurrently agreed by government. The authors describe the policy environment in the United States, United Kingdom and New Zealand which could provide useful information. In Australia the establishment of the Australian Screening Advisory Committee in 2001, now known as the Standing Committee on Screening has played an important role in providing guidance on what constitutes a good screening program through the development of the Population-Based Screening Framework in 2008. However, the authors believe that Australia is operating in an environment, which lacks a considered decision-making process for government, particularly in regards to assessing conditions for screening.
The authors believe that changes to newborn screening programs should be planned instead of being reactive often in response to new technologies. The authors provide several options to overcome the funding barrier, which they describe as chief obstacle, to developing and implementing a national decision-making framework for newborn screening in Australia. They believe that a national decision-making approach, supported by state implementation of decisions, would support consistent decision making across local-level programs.
Read the Open Access article
Patenting Genetic diagnostic methods
An article published in the Journal of Law and Medicine reviewed and analysed the relevant law in Australia and the United States to assist sponsors claiming patents for "diagnostic methods associated with genome-wide association studies (GWAS), adopting methodologies using next generation sequencing (NGS) and single nucleotide polymorphism (SNP)." The authors provide reasonable solutions to commonly experienced questions while patenting these technologies: experimental reproducibility and the credibility and veracity of the technology.
Read the Open Access article
Ethical, Legal & Social Issues
Living with Marfan syndrome: the patients view
A study published in Clinical Genetics explores the psychosocial aspects of Marfan syndrome (MFS) by collecting available literature followed by synthesising and critically appraising them. The authors studied 15 articles that satisfied the eligibility criteria and found that MFS significantly impacts various areas of the patient's life such as education, work, family and transition to adulthood. They also experienced decreased Health Related Quality of life, depression and anxiety. Interestingly, the authors also noted that the studies show there was a considerable disconnect between the discomfort that the patient experiences and how professionals view it. According to the authors the studies demonstrate that "the subjective perception of discomfort did not necessarily match the medical severity of a disease."
Consult the Pubmed abstract
New Syndromes
Developmental delay, microcephaly and hypomyelination associated with mutations in SLC1A4
Using exome analysis, the authors identified recessive mutations in SLC1A4 in ten Ashkenazi-Jewish patients from eight families who shared similar clinical features of developmental delay, microcephaly and hypomyelination. Seizure disorder was variably present.
Consult the Pubmed abstract
J Med Genet. ; 52(8):541-7 ; August 2015
Novel oculo-skeletal syndrome with intellectual disability caused by a MAB21L2 mutation
The authors described a novel recognizable phenotype characterized by anophthalmia, a distinctive skeletal dysplasia and intellectual disability in two unrelated individuals. Radiographic anomalies include severe rhizomelic shortness of the limbs and abnormal joint formation. Exome studies showed that these characteristics are part of the phenotypic spectrum of MAB21L2 gene mutations which cause a range of structural eye malformations such as microphthalmia/anophthalmia and ocular coloboma.
Consult the Pubmed abstract
Eur J Med Genet. ; 58(8):387-91 ; August 2015
Syndromic intellectual disability with variable clinical presentation due to mutations in DDX3X
The authors presented 35 unique deleterious de novo mutations in DDX3X identified by whole exome sequencing in 38 females with intellectual disability and various other features including hypotonia, movement disorders, behaviour problems, corpus callosum hypoplasia, and epilepsy. They also found missense variants in DDX3X in males from three families with intellectual disability suggestive of X-linked inheritance.
Consult the Pubmed abstract
Am J Hum Genet. ; 97(2):343-52 ; August 2015
Novel 3q28 microdeletion phenotype leading to haploinsufficiency of TP63
The authors reported on a 3-year-old male with intellectual disability, characteristic facial features, polydactyly and epilepsy carrying a paternally inherited 3q28 deletion leading to haploinsufficiency of TP63. The father, carrying the same deletion, presented with cleft palate, nail dystrophy and learning difficulties.
Consult the Pubmed abstract
Eur J Med Genet. ; 58(8):400-5 ; August 2015
New type of lysosomal storage disease characterized by spastic paraplegia, neuropathy, parkinsonism and/or cognitive impairment linked to AP5Z1 mutations
The authors characterized three independent fibroblast lines derived from skin biopsies of patients harbouring nonsense mutations in AP5Z1 and presenting with spastic paraplegia accompanied by neuropathy, parkinsonism and/or cognitive impairment.
Consult the Pubmed abstract
Hum Mol Genet. ; 24(17):4984-96 ; September 2015
Progressive myoclonus epilepsy with early ataxia caused by mutation of LMNB2
The authors studied a consanguineous Palestinian Arab family presenting an autosomal recessive progressive myoclonus epilepsy with early ataxia. A novel homozygous missense mutation was identified in LMNB2 that segregated with the progressive myoclonus epilepsy in the family.
Consult the Pubmed abstract
Hum Mol Genet. ; 24(16):4483-90 ; August 2015
Intellectual disability, hypotonia, epileptic susceptibility, frontal bossing, mild hypertelorism, and palpebral fissures caused by PPP2R5D and PPP2R1A mutations
The authors reported inherited dysregulation of protein phosphatase activity as a cause of intellectual disability. De novo missense mutations in PPP2R5D and PPP2R1A were identified in 16 individuals with mild to severe intellectual disability, long-lasting hypotonia, epileptic susceptibility, frontal bossing, mild hypertelorism, and downslanting palpebral fissures.
Consult the Pubmed abstract
J Clin Invest. ; 125(8):3051-62 ; August 2015
New Genes
Rett syndrome-like phenotype caused by a de novo deletion of PTPN4 in identical twins
Consult the Pubmed abstract
To read more about " Atypical Rett syndrome"
Eur J Hum Genet. ; 23(9):1171-5 ; September 2015
22q11.2 deletion syndrome: PRODH, ADNP2 and ZFPM2 involved in the phenotype
Consult the Pubmed abstract
To read more about " 22q11.2 deletion syndrome"
Hum Mutat. ; 36(8):797-807 ; August 2015
X-linked intellectual disability due to THOC2 mutations in four families
Consult the Pubmed abstract
Am J Hum Genet. ; 97(2):302-10 ; August 2015
Lethal ciliopathies ranging from hydrolethalus to short rib-polydactyly syndrome, Majewski type and Beemer-Langer type, caused by mutations in KIAA0586
Consult the Pubmed abstract
To read more about " Hydrolethalus"
To read more about " Short rib-polydactyly syndrome, Majewski type"
To read more about " Short rib-polydactyly syndrome, Beemer-Langer type"
Am J Hum Genet. ; 97(2):311-8 ; August 2015
Coenzyme Q10 deficiency linked to an alteration in COQ2 in a patient
Consult the Pubmed abstract
To read more about " Coenzyme Q10 deficiency"
Eur J Hum Genet. ; 23(9):1254-8 ; September 2015
Severe epileptic encephalopathy and complex movement disorder due to compound heterozygous mutations in CARS2 in a child
Consult the Pubmed abstract
J Med Genet. ; 52(8):532-40 ; August 2015
Overgrowth syndrome linked to de novo mutations in PPP2R5B, PPP2R5C and PPP2R5D
Consult the Pubmed abstract
To read more about " Overgrowth syndrome"
Hum Mol Genet. ; 24(17):4775-9 ; September 2015
Non-syndromic early-onset cone rod dystrophy associated with mutations in ALMS1 in a family
Consult the Pubmed abstract
To read more about " Cone rod dystrophy"
Hum Mutat. ; 36(9):836-41 ; September 2015
Megacystis-microcolon-intestinal hypoperistalsis syndrome caused by a homozygous loss-of-function variant in MYH11
Consult the Pubmed abstract
To read more about " Megacystis-microcolon-intestinal hypoperistalsis syndrome"
Eur J Hum Genet. ; 23(9):1266-8 ; September 2015
Heterotaxia and situs inversus totalis associated with a homozygous WDR16 deletion
Consult the Pubmed abstract
To read more about " Heterotaxia"
To read more about " Situs inversus totalis"
Eur J Hum Genet. ; 23(9):1262-5 ; September 2015
Familial idiopathic steroid-resistant nephrotic syndrome caused by COL4A3 mutations
Consult the Pubmed abstract
To read more about " Familial idiopathic steroid-resistant nephrotic syndrome"
Eur J Hum Genet. ; 23(9):1192-9 ; September 2015
Small cell lung cancer: somatic mutations in TP53, TP73 and RB1
Consult the Pubmed abstract
To read more about " Small cell lung cancer"
Nature ; 524(7563):47-53 ; August 2015
Clear cell sarcoma of the kidney due to consistent in-frame internal tandem duplications of BCOR
Consult the Pubmed abstract
Nat Genet. ; 47(8):861-3 ; August 2015
Fetal akinesia deformation sequence: homozygosity mapping in two fetuses revealed MUSK as a candidate gene
Consult the Pubmed abstract
To read more about " Fetal akinesia deformation sequence"
Eur J Hum Genet. ; 23(9):1151-7 ; September 2015
Language impairment, autism spectrum disorder and intellectual disability might be associated with ELP4 deletions
Consult the Pubmed abstract
Hum Mutat. ; 36(9):842-50 ; September 2015
Keratoconus: WNT10A exonic variant increases the risk of disease
Consult the Pubmed abstract
To read more about " Keratoconus"
Hum Mol Genet. ; 24(17):5060-8 ; September 2015
Research in Action
Clinical Research
Dravet syndrome: vaccination-associated seizure onset does not affect disease course, while the risk of subsequent vaccination associated seizures seems vaccine-specific
Consult the Pubmed abstract
To read more about " Dravet syndrome"
Neurology ; 85(7):596-603 ; August 2015
Progressive familial intrahepatic cholestasis type 2: improvement of cholestasis with 4-phenylbutyrate
Consult the Pubmed abstract
To read more about " Progressive familial intrahepatic cholestasis type 2"
Hepatology ; 62(2):558-66 ; August 2015
Alpha-1-antitrypsin deficiency: purified α1 proteinase inhibitor augmentation treatment slows progression of emphysema
Consult the Pubmed abstract
To read more about " Alpha-1-antitrypsin deficiency"
Lancet ; 386(9991):360-8 ; July 2015
Recessive dystrophic epidermolysis bullosa: promising efficacy and tolerance with systemic allogeneic mesenchymal stromal cell therapy
Consult the Pubmed abstract
Consult the study on Orphanet
To read more about " Recessive dystrophic epidermolysis bullosa-generalized other"
To read more about " Severe generalized recessive dystrophic epidermolysis bullosa"
J Invest Dermatol. ; 135(9):2319-21 ; September 2015
Facioscapulohumeral dystrophy: regular aerobic training with or without post-exercise protein-carbohydrate supplementation improves fitness
Consult the Pubmed abstract
To read more about " Facioscapulohumeral dystrophy"
Neurology ; 85(5):396-403 ; August 2015
Extranodal nasal NK/T cell lymphoma: Epstein-Barr virus latent membrane protein 1 and 2a transfer as a safe and effective post-remission therapy
Consult the Pubmed abstract
To read more about " Extranodal nasal NK/T cell lymphoma"
Mol Ther. ; 23(8):1401-9 ; August 2015
Biliary tract cancer: cediranib in combination with cisplatin and gemcitabine does not improve the progression-free survival of patients
Consult the Pubmed abstract
To read more about " Carcinoma of the ampulla of Vater"
To read more about " Cholangiocarcinoma"
To read more about " Carcinoma of gallbladder and extrahepatic biliary tract"
Lancet Oncol. ; 16(8):967-78 ; August 2015
Paraganglioma in pregnancy: a case series and review of the literature
Consult the Pubmed abstract
J Clin Endocrinol Metab. ; 100(8):3202-9 ; August 2015
Salla disease: 13-year follow-up of Finnish patients
Consult the Pubmed abstract
To read more about " Salla disease"
J Neurodev Disord. ; 7(1):20 ; 2015
Therapeutic Approaches
Jervell and Lange-Nielsen syndrome: review on human induced pluripotent stem cell models
Consult the abstract
To read more about " Jervell and Lange-Nielsen syndrome"
Rare Diseases ; 1(3) :1-4 ; 2015
Huntington disease: fingolimod enhances hippocampal synaptic plasticity and memory in mice
Consult the Pubmed abstract
To read more about " Huntington disease"
Hum Mol Genet. ; 24(17):4958-70 ; September 2015
Ebola hemorrhagic fever: aerosolized vaccine protects macaques exposed to the virus
Consult the Pubmed abstract
To read more about " Ebola hemorrhagic fever"
J Clin Invest. ; 125(8):3241-55 ; August 2015
Dystrophic epidermolysis bullosa: high local concentrations of intradermal mesenchymal stromal cells restore skin integrity and facilitate wound healing in a mouse model
Consult the Pubmed abstract
To read more about " Dystrophic epidermolysis bullosa"
Mol Ther. ; 23(8):1368-79 ; August 2015
Retinitis pigmentosa: ciliary neurotrophic factor gene therapy confers lifelong neuroprotection in a mouse model
Consult the Pubmed abstract
To read more about " Retinitis pigmentosa"
Mol Ther. ; 23(8):1308-19 ; August 2015
Leber congenital amaurosis and retinitis pigmentosa: mitigated results with adeno-associated virus-mediated gene therapy in mouse models
Consult the Pubmed abstract
To read more about " Leber congenital amaurosis"
To read more about " Retinitis pigmentosa"
Gene Ther. ; 22(8):619-27 ; August 2015
Duchenne muscular dystrophy: galectin-1 protein therapy prevents pathology and improves muscle function in the mdx mouse model
Consult the Pubmed abstract
To read more about " Duchenne muscular dystrophy"
Mol Ther. ; 23(8):1285-97 ; August 2015
Steinert myotonic dystrophy: recombinant adeno-associated viral vectors injected intravenously reduce disease pathology in muscles of mice
Consult the Pubmed abstract
To read more about " Steinert myotonic dystrophy"
Hum Mol Genet. ; 24(17):4971-83 ; September 2015
Fragile X-associated tremor/ataxia syndrome: new inducible mouse model
Consult the Pubmed abstract
To read more about " Fragile X-associated tremor/ataxia syndrome"
Hum Mol Genet. ; 24(17):4948-57 ; September 2015
Diagnostic Approaches
Walker-Warburg syndrome: chromosomal microarray analysis as a first-line diagnostic test in patients with a fetus with one or more major structural abnormalities identified
Consult the Pubmed abstract
To read more about " Walker-Warburg syndrome"
Eur J Med Genet. ; 58(8):372-5 ; August 2015
Distinct optical coherence tomography patterns clearly differentiates Susac syndrome from relapsing-remitting multiple sclerosis
Consult the Pubmed abstract
To read more about " Susac syndrome"
Neurology ; 85(7):610-8 ; August 2015
CARASIL: characteristic features and progression of abnormalities on magnetic resonance imaging
Consult the Pubmed abstract
To read more about " CARASIL"
Neurology ; 85(5):459-63 ; August 2015
Patient Management and Therapy
Cystic fibrosis: review on tiotropium bromide and tobramycin for the treatment
Consult the fisrt abstract
Consult the second abstract
To read more about " Cystic fibrosis"
Expert Opinion on Orphan Drugs. ; 3(8):957-966; 3(8):933-943 ; August 2015
Fanconi anemia: review on gene therapy
Consult the abstract
To read more about " Fanconi anemia"
Expert Opinion on Orphan Drugs. ; 3(8):899-910 ; August 2015
Lymphangioleiomyomatosis: review on new treatments
Consult the Pubmed abstract
To read more about " Lymphangioleiomyomatosis"
Lung ; 193(4):467-75 ; August 2015
Blepharospasm: review on alternatives to botulinum toxin for the management Id:
Consult the abstract
Expert Opinion on Orphan Drugs ; 3(8):877-885 ; August 2015
Congenital hyperinsulinism: review on molecular mechanisms, therapeutic targets and management
Consult the first abstract
Consult the second abstract
To read more about " Congenital isolated hyperinsulinism"
Expert Opinion on Orphan Drugs ; 3(8):887-898 ; August 2015Research and Reports in Endocrine Disorders ; (5):103-117 ; July 2015
Kawasaki disease: a review
Consult the Pubmed abstract
To read more about " Kawasaki disease"
Nat Rev Rheumatol. ; 11(8):475-82 ; August 2015
Paediatric rheumatology: review on lessons from oncology to optimize treatment
Consult the Pubmed abstract
Nat Rev Rheumatol. ; 11(8):493-9 ; August 2015
Metachromatic leukodystrophy: review on hematopoietic stem cell transplantation
Consult the abstract
To read more about " Metachromatic leukodystrophy"
Expert Opinion on Orphan Drugs ; 3(8):911-919 ; August 2015
B-cell non-Hodgkin lymphoma: review on the treatment
Consult the abstract
To read more about " B-cell non-Hodgkin lymphoma"
Expert Opinion on Orphan Drugs ; 3(8):921-932 ; August 2015
Huntington disease: a review
Consult the abstract
To read more about " Huntington disease"
Rare Diseases ; Volume 3, Issue 1 ; 2015
MECP2 disorders: a review
Consult the Pubmed abstract
To read more about " Trisomy Xq28"
To read more about " Rett syndrome"
J Clin Invest. ; 125(8):2914-23 ; August 2015
Glycogen storage disease due to acid maltase deficiency: a review
Consult the abstract
To read more about " Glycogen storage disease due to acid maltase deficiency"
Rare Diseases ; Volume 3, Issue 1 ; 2015
Congenital generalized lipodystrophies: a review
Consult the Pubmed abstract
Nat Rev Endocrinol. ; 11(9):522-34 ; September 2015
Ribosomopathies: a review
Consult the abstract
Rare Diseases ; Volume 3, Issue 1 ; 2015
Duchenne muscular dystrophy: a review
Consult the abstract
To read more about " Duchenne muscular dystrophy"
Rare Diseases ; Volume 3, Issue 1 ; 2015
Familial dilated cardiomyopathy: review on diagnosis, prevalence and screening
Consult the abstract
To read more about " Familial dilated cardiomyopathy"
Expert Opinion on Orphan Drugs ; 3(8):869-876 ; August 2015
Tuberous sclerosis: review on pathophysiology
Consult the abstract
To read more about " Tuberous sclerosis"
Rare Diseases ; Volume 3, Issue 1 ; 2015
West-Nile encephalitis: a review
Consult the Pubmed abstract
To read more about " West-Nile encephalitis"
Lancet Infect Dis. ; 15(8):951-9 ; August 2015
Idiopathic interstitial pneumonias with connective tissue diseases features: a review
Consult the Pubmed abstract
Respirology ; [Epub ahead of print] ; July 2015
Primary biliary cirrhosis and primary sclerosing cholangitis: a review
Consult the Pubmed abstract
To read more about " Primary biliary cirrhosis"
To read more about " Primary sclerosing cholangitis"
Hepatology ; 62(2):635-43 ; August 2015
Eosinophilic esophagitis and gastroenteritis: a review
Consult the Pubmed abstract
To read more about " Eosinophilic esophagitis"
To read more about " Eosinophilic gastroenteritis"
To read more about " Eosinophilic colitis"
Curr Allergy Asthma Rep. ; 15(9):558 ; September 2015
T-cell large granular lymphocyte leukemia: review on pathogenesis and treatment
Consult the abstract
To read more about " T-cell large granular lymphocyte leukemia"
Expert Opinion on Orphan Drugs ; 3(8):859-867 ; August 2015
One new and nine updated GeneReviews published
GeneReviews are expert-authored, peer-reviewed disease descriptions ("chapters") presented in a standardized format and focused on clinically relevant and medically actionable information on the diagnosis, management, and genetic counseling of patients and families with specific inherited conditions. One new GeneReviews has been published for:
Lysosomal acid lipase deficiency
Nine updated GeneReviews have been published for:
Cartilage-hair hypoplasia – anauxetic dysplasia spectrum disorders
Andersen-Tawil syndrome
EZH2-related overgrowth
Hereditary leiomyomatosis and renal cell cancer
Myotonia congenita
TP63-related disorders
Von Hippel-Lindau syndrome
Mucolipidosis IV
OTOF-related deafness
Orphan Drugs
Analysing the ability of fulfilling the obligations of conditionally approved drugs in Europe
Since the introduction of conditional marketing authorisation by the European Medicines Agency in 2004, patients have gained access to drugs which fulfil an urgent and unmet need. A paper published in European Journal of Internal Medicine examines whether the conditionally approved drugs manage to obtain comprehensive evidence confirming that the risk-benefit balance is positive to obtain full marketing authorisation and the time taken to reach it.
The authors identified 24 products conditionally authorised for sale, between the years 2006-2015, out of which 9 were orphan drugs and 3 had orphan status. Till date 10 medicinal products have been switched to regular approval while 14 of them are still under conditional approval.
The authors demonstrate that the median time for the ten conditional approvals to finish their specific obligations and switch to regular marketing authorisations was five years, noting delays, discrepancies and lack of information on some of these drugs.
Overall, the median time allowed to address the specific obligations is four years. The median time to fulfil obligations for drugs still conditional is nearly twice that of those converted. Of the 14 medicinal products still under conditional approval, nine have specific obligations whose timeframes go beyond 2015 but some of these did not have up-to-date information on the trials that need to conducted to address the obligations. Out of the drugs that have to fulfil their obligations this year, almost all of them have delays and discrepancies.
From the data gathered the authors caution that the conditionally approved drugs without fully established clinical value are in the market for long periods and question whether the public health advantage outweigh the risks of limited clinical information.
Consult the Pubmed abstract
Wanted: new models of pricing and reimbursement for gene therapies
The debate on pricing and reimbursement is currently rife, especially in the area of rare diseases. Gene therapy and its pricing add another layer of complexity as discussed in an article published in Nature Biotechnology (discussed in OrphaNews) on Glybera – a gene therapy with a whopping €1.1 million price tag for a one-time treatment. In the same journal, how the 'payers,' either public or private, are concerned with both the price levels routinely mentioned for gene therapies and the pricing and reimbursement (P&R) approaches is discussed in a Letter to the Editor.
The authors contacted payers in the United States and Western Europe to identify their top two choices for payment. They report that in the absence of health system constraints, payers prefer annuities as it reduces initial financial strain, leadS to predictable yearly budget impact and reflect the ongoing value of gene therapy. However, the authors point out that in the real world, approaches based on a lump sum payment represent the large majority. According to the authors payers might accept high price tags for gene therapies if industry develops sound and rational pricing & reimbursement approaches based on payer perceived value. The survey demonstrated that payers preferred that gene-therapy reimbursements should model organ transplants procedures (a one-time procedure) rather than protein-replacement therapy (requires frequent dosage).
The article suggests a new era in pharmaceutical economics where 'cost-effectiveness' may not necessarily be equated with 'affordability'.
Access the Letter to the Editor
Regulatory News
FDA approves new orphan drug to treat 20 patients worldwide
The U.S. Food and Drug Administration (FDA) approved Xuriden (uridine triacetate), the first FDA approved treatment for patients with hereditary orotic aciduria. Hereditary orotic aciduria is a rare metabolic disorder, which has been reported in approximately 20 patients worldwide.
Hereditary orotic aciduria is inherited from a recessive gene. The disease is due to a defective or deficient enzyme, which results in the body being unable to normally synthesise uridine. Signs and symptoms of the disease include blood abnormalities, urinary tract obstruction, failure to thrive, and developmental delays. The approval of this drug was based on the results from a 4‑patient 6‑week clinical trial with a 6‑month extension phase. Wellstat - the sponsor of this drug has not yet disclosed the price of this ultra orphan drug
Read the FDA press release
New treatment option for patients with multiple myeloma
The European Medicines Agency (EMA) has recommended granting a marketing authorisation for Kyprolis (carfilzomib) to treat patients with multiple myeloma whose disease has relapsed (i.e. the cancer has come back after receiving at least one prior course of therapy). Kyprolis is for use in combination with the cancer medicines lenalidomide and dexamethasone. Multiple myeloma is a rare and life-threatening cancer of a type of white blood cell, called plasma cells, which originate in the bone marrow. Carfilzomib is the first irreversible, highly-selective, proteasome inhibitor for multiple myeloma. The irreversible binding to the targeted proteasome leads to a more sustained inhibition with minimal inhibition of other non-targeted enzymes.
Read the EMA press release
Grants
Medical Research Grant Application Guidelines : Progeria Research Foundation
The foundation is proving several grants such as Innovator Awards, Established Innovator Award, and Specialty Award. Details are provided on their website
AFM Telethon: Call for proposals
Several call for proposals are being made available by AFM Telethon. They have published a call for proposals for Spinal Muscular Atrophy and Collagen VI Call for Projects.
For further information
Neuronal Ceroid Lipofuscinosis Research Award
For the sixth time the Foundation announces and donates the NCL Research Award. They invite medical and basic science researchers worldwide to submit innovative project proposals that are either clinically oriented or cover translational aspects of CLN3 biology which can contribute to finding a cure for juvenile NCL. We particularly encourage also submissions from scientists working in related biomedical areas such as other lysosomal storage diseases, endolysosomal cell biology and neurodegenerative disorders. Together with the existing NCL research community our goal is to move promising therapeutic avenues forward to help JNCL patients. The grant (50,000 euros) serves as seed money supporting a one year postdoctoral fellowship to help young scientists progressing CLN3 research in academia or industry. Deadline: October 31, 2015
For further information
BMBF Funding initiative: innovative stem cell technologies for personalized medicine
The German Federal Ministry for Education and Research (BMBF) has announced a new funding initiative for the development and use of innovative stem cell technologies. The initiative aims at funding interdisciplinary research collaborations which are geared towards unlocking the full potential of novel reprogramming technologies and iPS cells for practical use. For this, a pooling of expertise from applied basic and clinical research is needed, for example of research groups from the life sciences, medicine, pharmacology and relevant technical disciplines. The funding can be applied for in two modules: "therapy" and "model & test systems". Deadline for applications is 30 November 2015.
More information (in German)
8th Call for SMA research proposals
This Call is open to any research project aimed at finding a therapy for Spinal Muscular Atrophy (SMA) or elucidating the basic pathophysiological processes of the disease. SMA‐Europe aims to help the international scientific and medical community in its search for therapies for SMA. Preferences will be given to projects with the greatest potential to overcome barriers to translate science into effective treatments.
Two types of research grants will be awarded for up to two years:
1. Operating Grants
2. Postdoctoral Fellowship
Application deadline: 9 December 2015
For further information
Partnersearch, Job Opportunities
ECRIN ERIC job vacancies
ECRIN‐Eric is currently in the process of recruiting for its office based in Paris (France) a Capacity Project Manager, an Operations Project Manager and a Secretary. This is a unique opportunity for a motivated individual who wishes to further develop his/her career in biomedical research and his/her experience of multinational research projects. The ECRIN Capacity Project Manager will be in charge of the project management for the structuring projects with ECRIN involvement.
For further information
Civil Society representatives: Call for expression of interest is open for the EMA Management Board
The Commission is launching a selection procedure to appoint the Civil Society representatives in the Management Board of the European Medicines Agency (EMA), in London. Four members from Civil Society will be appointed: two members representing patients' organisations, one member representing doctors' organisations and one member representing veterinarians' organisations. The term of office of the current members expires on 20 March 2016.
For further information
Courses & Educational Initiatives
The 2nd Biennial Australian Rare Lung Disease Short Course
Date: 16-17 October, 2015
Venue: Sydney, Australia
The joint venture between Lung Foundation Australia and the Thoracic Society of Australia and New Zealand (TSANZ) will provide updates on the latest in research, diagnosis, therapy and care for Interstitial Lung Disease. The program boasts an exceptional selection of Australian specialists as well as keynote presentations from international speaker, Professor Kevin Flaherty (USA). For further information or to register please visit: www.lungfoundation.com.au
Courses offered by Recordati Rare Diseases Foundation
The Recordati Rare Diseases Foundation is offering five courses planned for next year. For further information, please contact Cecilia Kellquist, Coordinator and member of the board, ckellquist@rrd-foundation.org/www.rrd-foundation.org.
Neurotransmitter focus course
Date: 9-10 November 2015
Venue: Venice, Italy
in partnership with University Hospital for Child and Adolescent Medicine of Heidelberg and University Hospital of Padua. Registration deadline: 26th September
EMA workshop on demonstrating significant benefit of orphan medicines
Date: 7 December, 2015
Venue: London, United Kingdom
The European Medicines Agency (EMA) is organising a workshop on 7 December 2015 to discuss the approach that should be followed by medicine developers to demonstrate the significant benefit of an orphan medicine over existing treatments. Demonstrating a significant benefit is one of the criteria medicines that treat rare diseases must fulfil to benefit from 10 years of market exclusivity once they have been authorised.
The workshop will bring together medicine developers, regulators, healthcare professionals, academia, patients, health technology assessment bodies and healthcare payers who need to register by 31 October 2015 if they wish to participate. The workshop will also be broadcast live.
For further information
European Cytogenetesists Association
Date: February/March of each year
Venue: Nimes, France
This course is designed to provide advanced training in constitutional, haematological, and oncological cytogenetics to medical graduates, pharmacists, pathologists, biologists, health professionals and researchers, with an academic qualification. The students will be trained to identify genetic abnormalities for diagnosis and prognosis, and for fundamental and applied research using both classical and molecular cytogenetic techniques. The course is co-organized by E.C.A. and two French Universities, either as a stand-alone course with only the theoretical part or as a University Diploma including both theoretical and practical training. An application for CME points will also be made for 2016.
For further information
EMA workshop on pre-licencing activities
Date: 9 March, 2016
Venue: Barcelona, Spain
In collaboration with EMA, E-Rare will organize a workshop dedicated to Interactions between EMA and RD researchers on pre-licensing activities. The workshop will take place from 09:00 to 16:00 on the 9 of March 2015 in Barcelona, before the official start of the RE(ACT) meeting. It will be open to all researchers and interested stakeholders.
The places for Face-to-face meetings with EMA officers are limited! If you would like to participate, please send an email to juliane.halftermeyer@agencerecherche.fr for further instructions.
What's on Where?
CLIMB Newborn Screening Conference
Date: 10 October, 2015
Venue: Birmingham, UK
The CLIMB Newborn Screening Conference will be exploring four new conditions on the newborn screening programme, as well as current metabolic conditions. Midwives will have the opportunity to find out more about conditions that affect infants, including MCADD, PKU, Maple Syrup Disease and Glutaric Aciduria Type 1.
For further information
Xth Annual ICORD Meeting, part of the Global Rare Diseases Week, Mexico
Date: 15-16 October (ICORD), 12-16 October (Global Rare Disease Week, Mexico)
Venue: Mexico City, Mexico
ICORD 2015 will be held in México FD (México) 15-16 October in association with FEMEXER (the Mexican Federation of Rare Diseases) and GEISER Foundation (the Group of Linkage, Research and Support for Rare Diseases in Latin America). The event is part of the "Global Rare Diseases Week, Mexico 2015″ and back to back with the 4th Latin American meeting of Rare Diseases on October 12 and the Discoveries and Innovations in Orphan Drugs Congress, October 13-14.
For further information
6th South Eastern European Cystic Fibrosis Conference
Date: 19-20 October, 2015
Venue: Bucharest, Romania
This regional conference is a 2‐day symposium in Romania, addressing physicians, allied health professionals and patient representatives from the South Eastern European and Mediterranean region.
For further information
NORD Summit
Date: 21-22 October, 2015
Venue: Virginia, United States
The 2015 Breakthrough Summit is concentrated with innovative content and convenes the top leaders from the FDA, NIH, Industry, Patient Groups, Payers and Research Institutions to address the progress of rare disease diagnosis, genomics, drug development, patient engagement, patient-centered research models, product approva ls, FDA oversight and market access to orphan products.
For further information
13th Annual Congress Of International Drug Discovery Science & Technology, Therapy And Expo‐2015
Date: 20-22 October, 2015
Venue: Beijing, China
This conference will provide a unique opportunity for researchers from all over the world to meet, network, and forge new scientific interactions.
For further information
The BioData World Congress 2015
Date: 21-22 October, 2015
Venue: Cambridge, United Kingdom
This conference is held with the support of Intel, The Wellcome Trust Sanger Institute, The European Bioinformatics Institute, The Babraham Institute, BIA, BioNow, The Pharmacogenetics and Stratified Medicine Network and the Pistoia Alliance, BioData World Congress.
For further information
6th World Congress on Targeting Mitochondria
Date: 21-22 October, 2015
Venue: Berlin, Germany
This 6th World Congress on Targeting Mitochondria will cover a variety of new strategies and innovations as well as clinical applications in Mitochondrial Medicine.
For further information
The AANEM Annual Meeting
Date: 28 -31 October, 2015
Venue: Hawaii, United States
The AANEM Annual Meeting is the premier educational event for those involved in neuromuscular (NM) and electrodiagnostic (EDX) medicine. Earn over 30 continuing education credits through interactive workshops, lively discussions, and engaging sessions.
For further information
4th European Congress on Rett Syndrome
Date: 30 October – 1 November, 2015
Venue: Rome, Italy
For further information
First European Congress on Hereditary ATTR amyloidosis ECATTR
Date: 2-3 November, 2015
Venue: Paris, France
The European Congress for HATTR will allow the meeting of the specialists of all European countries and the sharing of experience. The effort will be to further improve the early diagnosis of sporadic cases and genetic carriers, to review anti-amyloid treatments and clinical trials, to improve genetic counselling.
For further information
2nd International Primary Immunodeficiencies Congress (IPIC)
Date: 5-6 November, 2015
Venue: Budapest, Hungary
The International Patient Organisation for Primary Immunodeficiencies (IPOPI) announces the Second International Primary Immunodeficiencies Congress (IPIC). This event will build on the successful outcomes of the first IPIC, attended by 400 participants. The congress will consist of a two-day programme and is open to all stakeholders with an interest in clinical management of primary immunodeficiencies (PIDs).
For further information
Sixth Croatian Congress of Human Genetics
Date: 5-7 November, 2015
Venue: Zagreb, Croatia
This conference will be an opportunity for education of the young interested in new achievements in various areas of genetics – clinical genetics, cytogenetics, molecular genetics and anthropology, and also to highlight the importance of prevention, diagnostics and treatment of rare diseases.
For further information
16th International Conference on Human Genome Variation and Complex Genome Analysis
Date: 11-13 November, 2015
Venue: California, United States
HGV2015 will bring together approximately 180 delegates (selected on the basis of their abstract submission) in a workshop-style atmosphere, with 25 internationally recognized speakers.
For further information
Statistical analysis of massive genomic data
Date: 19-20 November, 2015
Venue: Evry, France
This two-day cross-disciplinary conference will bring together biologists, geneticists, clinicians, bioinformaticians and statisticians in order to discuss emerging challenges raised by the analysis of high-throughput genomic data, and present dedicated innovative approaches.
For further information
The Rett Syndrome Journey: Pathways to Follow
Date: 19-21 November, 2015
Venue: Victoria, Australia
'Pathways to Follow' on the journey with Rett syndrome will be explored in such areas as communication, health, therapies, education, equipment, caring for the carer, Commonwealth government, trusts, siblings, adulthood, family and equipment, to name just a few.
For further information
6th European Symposium on rare anaemias - 1st Dutch-Belgian meeting for patients and health professionals
Date: 21-22 November, 2015
Venue: Amsterdam, The Netherlands
The 6th European Symposium on Rare Anaemias is an activity of the ENERCA project which aims to disseminate up-to-date knowledge and increase the public awareness about congenital and rare anaemias. This year, transversal topics centered on common medical problems of patients with sickle cell, thalassaemia and other forms of haemolytic anaemia will be one of the key points of the symposium.
For further information
International Conference on Sanfilippo Syndrome and related Lysosmal Storage Diseases
Date: 26 – 28 November, 2015
Venue: Geneva, Switzerland
The aim of this second unique forum is to bring together some 200 participants from around the world, including scientists and clinicians, start-up leaders, and families of patients groups, to inform and strengthen exchange and cooperation.
For further information
Clinical trials in small populations : Methodological challenges and solutions
Date: 30th November - 1 December 2015
Venue: London, UK
The movement towards genetically tailored treatment regimens will further increase the number of small populations for whom new treatments are sought. This two day meeting will bring together researchers and practitioners to discuss state of the art methods for trials in small populations.
For further information
CDDF-SIOPE-ENCCA-ITCC 4th Paediatric Oncology Conference
Date: 9-10 January, 2016
Venue: Brussels, Belgium
This is the fourth meeting of an ongoing series of biennial conferences aiming at promoting progress in the field of paediatric oncology drug development through input from all concerned stakeholders: regulatory bodies, academia, the pharmaceutical industry, parents and policymakers.
For further information
CDDF-SIOPE-ENCCA-ITCC 4th Paediatric Oncology Conference
Date: 9-10 January, 2016
Venue: Brussels, Belgium
This is the fourth meeting of an ongoing series of biennial conferences aiming at promoting progress in the field of paediatric oncology drug development through input from all concerned stakeholders: regulatory bodies, academia, the pharmaceutical industry, parents and policymakers.
For further information
BPSU Rare Disease Conference 2016
Date: 23 February, 2016
Venue: Birmingham, United Kingdom
The conference will explore the theme 'Rare disease in paediatrics – from birth to transition'. It will centre on the child's journey from diagnosis through transition and end of life care.
For further information
Clinical Innovation & Outsourcing
Date: 9-10 March, 2016
Venue: London, UK
Clinical Outsourcing & Partnering World is the largest industry event focusing on the strategic and operational considerations in clinical outsourcing. It is a place where serious business contacts are made. Attended by senior decision makers, it's a platform which facilitates meetings between your sales force and prospects and it's a cost effective sponsorship package with year round advantage.
For further information
The RE(ACT) Congress
Date: 9-10 March, 2016
Venue: Barcelona, Spain
The congress aims to bring together world leaders and young scientist from a variety of breaking through scientific field to present cutting edge research, to discuss results and to exchange ideas. Moreover, many patients and patient organization, which are committed in research, will be present to share their experience.
For further information
MYOLOGY 2016 Fifth International Congress of Myology
Date: 14-18 March, 2016
Venue: Lyon, France
Held for the first time in 2000, MYOLOGY has become a unique opportunity for international experts in the field to exchange and confront the emerging therapeutic approaches, but also to share the first clinical results. The science and medicine of muscle have reached a new milestone. In Myology 2016, no doubt there will be new results, new breakthroughs to share all together.
For further information
13th International Congress of Human Genetics (ICHG) 2016
Date: 3-7 April, 2016
Venue: Kyoto, Japan
Hosted by the East-Asian Union of Human Genetic Societies (EAUHGS) and the Japan Society of Human Genetics, the 13th ICHG will focus on progress in genome analysis technologies and big data in order to explore disease mechanisms and treatment opportunities. Registrations open in 2015.
For further information
8th Alstrom Syndrome International Conference
Date: 12-16 May, 2016
Venue: Massachusetts, USA
This international conference will have a scientific symposium for clinicians and researchers as well as sessions for parents, caretakers and patient organisations.
For further information
17th EMSOS Nurse and allied professional Group Meeting
Date: 12-16 May, 2016
Venue: Massachusetts, USA
The meeting will be focussing on Ewing sarcoma, margins, pelvic tumours, targeted therapy; open sessions will offer the opportunity to report and discuss the latest results in all fields.
For further information
European Association of Centres of Medical Ethics Conference
Date: 8 -10 September, 2016
Venue: Leuven; Belgium
The focus of this year's conference is on a variety of highly relevant ethical issues in health care:
Organizational Ethics in Health Care: Principles, Cases and Practical Solutions
Ethical Issues in Care for Older Persons
Ethical, Legal and Social Developments in Human Genomics
Ethics and Integrity in Research
For further information
9th ISNS International meeting/10th ISNS European Regional meeting
Date: 11-14 September, 2016
Venue: The Hague, the Netherlands
The conference will aid the sharing of neonatal screening experiences for congenital metabolic disorders, its clinical diagnostics and follow-up, and will facilitate learning from other experiences. The programme will consist of plenary lectures, oral presentations and poster sessions and will be attractive for professionals, patient/advocacy groups, policy makers and industrial partners. The programme will include evaluation of performance of neonatal screening systems and strategies for improvement.
For further information
ESID European Society for Immunodeficiencies: Biennial meeting
Date: 21-24 September, 2016
Venue: Barcelona, Spain
Sessions at this meeting will be devoted to understanding primary immunodeficiencies and their clinical aspects.
For further information
Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182,6932607174
|
Read More »
Neural Regeneration Research
Neuroinflammation and comorbidities are frequently ignored factors in CNS pathology
Raluca Elena Sandu, Ana Maria Buga, Adriana Uzoni, Eugen Bogdan Petcu, Aurel Popa-Wagner
Neural Regeneration Research 2015 10(9):1349-1355
Virtually all drug interventions that have been successful pre-clinically in experimental stroke have failed to prove their efficacy in a clinical setting. This could be partly explained by the complexity and heterogeneity of human diseases as well as the associated co-morbidities which may render neuroprotective drugs less efficacious in clinical practice. One aspect of crucial importance in the physiopathology of stroke which is not completely understood is neuroinflammation. At the present time, it is becoming evident that subtle, but continuous neuroinflammation can provide the ground for disorders such as cerebral small vessel disease. Moreover, advanced aging and a number of highly prevalent risk factors such as obesity, hypertension, diabetes and atherosclerosis could act as "silent contributors" promoting a chronic proinflammatory state. This could aggravate the outcome of various pathological entities and can contribute to a number of subsequent post-stroke complications such as dementia, depression and neurodegeneration creating a pathological vicious cycle. Moreover, recent data suggests that the inflammatory process might be closely linked with multiple neurodegenerative pathways related to depression. In addition, pro-inflammatory cytokines could play a central role in the pathophysiology of both depression and dementia. |
Cell replacement therapy for central nervous system diseases
Danju Tso, Randall D McKinnon
Neural Regeneration Research 2015 10(9):1356-1358
The brain and spinal cord can not replace neurons or supporting glia that are lost through traumatic injury or disease. In pre-clinical studies, however, neural stem and progenitor cell transplants can promote functional recovery. Thus the central nervous system is repair competent but lacks endogenous stem cell resources. To make transplants clinically feasible, this field needs a source of histocompatible, ethically acceptable and non-tumorgenic cells. One strategy to generate patient-specific replacement cells is to reprogram autologous cells such as fibroblasts into pluripotent stem cells which can then be differentiated into the required cell grafts. However, the utility of pluripotent cell derived grafts is limited since they can retain founder cells with intrinsic neoplastic potential. A recent extension of this technology directly reprograms fibroblasts into the final graftable cells without an induced pluripotent stem cell intermediate, avoiding the pluripotent caveat. For both types of reprogramming the conversion efficiency is very low resulting in the need to amplify the cells in culture which can lead to chromosomal instability and neoplasia. Thus to make reprogramming biology clinically feasible, we must improve the efficiency. The ultimate source of replacement cells may reside in directly reprogramming accessible cells within the brain. |
Enhancing endogenous stem cells in the newborn via delayed umbilical cord clamping
Christopher Lawton, Sandra Acosta, Nate Watson, Chiara Gonzales-Portillo, Theo Diamandis, Naoki Tajiri, Yuji Kaneko, Paul R Sanberg, Cesar V Borlongan
Neural Regeneration Research 2015 10(9):1359-1362
There is currently no consensus among clinicians and scientists over the appropriate or optimal timing for umbilical cord clamping. However, many clinical studies have suggested that delayed cord clamping is associated with various neonatal benefits including increased blood volume, reduced need for blood transfusion, increased cerebral oxygenation in pre-term infants, and decreased frequency of iron deficiency anemia in term infants. Human umbilical cord blood contains significant amounts of stem and progenitor cells and is currently used in the treatment of several life-threatening diseases. We propose that delayed cord clamping be encouraged as it enhances blood flow from the placenta to the neonate, which is accompanied by an increase supply of valuable stem and progenitor cells, as well as may improve blood oxygenation and increase blood volume, altogether reducing the infant's susceptibility to both neonatal and age-related diseases. |
PTEN inhibition and axon regeneration and neural repair
Yosuke Ohtake, Umar Hayat, Shuxin Li
Neural Regeneration Research 2015 10(9):1363-1368
The intrinsic growth ability of all the neurons declines during development although some may grow better than others. Numerous intracellular signaling proteins and transcription factors have been shown to regulate the intrinsic growth capacity in mature neurons. Among them, PI3 kinase/Akt pathway is important for controlling axon elongation. As a negative regulator of this pathway, the tumor suppressor phosphatase and tensin homolog (PTEN) appears critical to control the regenerative ability of young and adult neurons. This review will focus on recent research progress in axon regeneration and neural repair by PTEN inhibition and therapeutic potential of blocking this phosphatase for neurological disorders. Inhibition of PTEN by deletion in conditional knockout mice, knockdown by short-hairpin RNA, or blockade by pharmacological approaches, including administration of selective PTEN antagonist peptides, stimulates various degrees of axon regrowth in juvenile or adult rodents with central nervous system injuries. Importantly, post-injury PTEN suppression could enhance axonal growth and functional recovery in adult central nervous system after injury. |
The choline pathway as a strategy to promote central nervous system (CNS) remyelination
Thomas Skripuletz, Ralf A Linker, Martin Stangel
Neural Regeneration Research 2015 10(9):1369-1370 |
Non-steroidal anti-inflammatory drugs (NSAIDs) and neuroprotection in the elderly: a view from the mitochondria
María Calvo-Rodríguez, Lucía Núñez, Carlos Villalobos
Neural Regeneration Research 2015 10(9):1371-1372 |
Neural correlates of the Heidelberg Music Therapy: indicators for the regeneration of auditory cortex in tinnitus patients?
Christoph M Krick, Heike Argstatter
Neural Regeneration Research 2015 10(9):1373-1375 |
Neurochemical plasticity of Müller cells after retinal injury: overexpression of GAT-3 may potentiate excitotoxicity
Clarissa S Schitine, Fernando G de Mello, Ricardo A.M. Reis
Neural Regeneration Research 2015 10(9):1376-1378 |
Can progesterone be a better alternative to dexamethasone for use in routine brain surgery?
Stephen Y Cheng, Gilberto K. K. Leung
Neural Regeneration Research 2015 10(9):1379-1380 |
Adipose-brain crosstalk: do adipokines have a role in neuroprotection?
Jonathan P Little, Adeel Safdar
Neural Regeneration Research 2015 10(9):1381-1382 |
Read More »
Rare DiseaseS
| OrphaNews Europe : 10 October 2015 |
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| Editorial |
| RD-ACTION: the new European Joint Action |
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| Spotlight on... |
| Working for rare diseases: EUCERD Joint Action draws to a close and looks to the future |
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| EU Policy News |
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| EMA |
| Submit expressions of interest to represent civil society at the EMA |
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| National & International Policy Developments |
| Comprehensive policy for patients with rare diseases in Philippines |
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| Other European news |
| The rare disease persons card implementation in Portugal |
| Sample of the adult British population want genetic testing of children for adult-onset conditions |
| Sample of Danish population want disclosure of incidental findings from NGS studies |
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| Other International News |
| Discussion paper by the Australian government to support people with chronic and complex health conditions |
| Contradictions of public health policies geared to rare disorders in Brazil |
| Sickle cell disease among children in Africa |
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| Guidance Documents and Recommendations |
| 22q11.2 deletion syndrome: guidelines for the management |
| Cushing syndrome: guidelines on treatment |
| Congenital hypogonadotropic hypogonadism: European consensus statement on diagnosis and treatment |
| Pemphigus vulgaris/foliaceus and bullous pemphigoid: guidelines for the treatment |
| Facioscapulohumeral dystrophy: guidelines on evaluation, diagnosis and management |
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| Bioinformatics, Registries and Data Management |
| How do paediatric biobanks look at various aspects of obtaining consent from the paediatric population |
| Long tail economics and rare disease research: the impact of next generation sequencing for rare mendelian disorders |
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| Screening and Testing |
| Regulating laboratory developed tests in the United States: the current controversy |
| Article reviewing the limits of FDA's authority to regulate laboratory developed diagnostic tests |
| Newborn screening in Australia: current environment and future perspectives |
| Patenting Genetic diagnostic methods |
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| Ethical, Legal & Social Issues |
| Living with Marfan syndrome: the patients view |
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| New Syndromes |
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| Developmental delay, microcephaly and hypomyelination associated with mutations in SLC1A4 |
| Novel oculo-skeletal syndrome with intellectual disability caused by a MAB21L2 mutation |
| Syndromic intellectual disability with variable clinical presentation due to mutations in DDX3X |
| Novel 3q28 microdeletion phenotype leading to haploinsufficiency of TP63 |
| New type of lysosomal storage disease characterized by spastic paraplegia, neuropathy, parkinsonism and/or cognitive impairment linked to AP5Z1 mutations |
| Progressive myoclonus epilepsy with early ataxia caused by mutation of LMNB2 |
| Intellectual disability, hypotonia, epileptic susceptibility, frontal bossing, mild hypertelorism, and palpebral fissures caused by PPP2R5D and PPP2R1A mutations |
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| New Genes |
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| Rett syndrome-like phenotype caused by a de novo deletion of PTPN4 in identical twins |
| 22q11.2 deletion syndrome: PRODH, ADNP2 and ZFPM2 involved in the phenotype |
| X-linked intellectual disability due to THOC2 mutations in four families |
| Lethal ciliopathies ranging from hydrolethalus to short rib-polydactyly syndrome, Majewski type and Beemer-Langer type, caused by mutations in KIAA0586 |
| Coenzyme Q10 deficiency linked to an alteration in COQ2 in a patient |
| Severe epileptic encephalopathy and complex movement disorder due to compound heterozygous mutations in CARS2 in a child |
| Overgrowth syndrome linked to de novo mutations in PPP2R5B, PPP2R5C and PPP2R5D |
| Non-syndromic early-onset cone rod dystrophy associated with mutations in ALMS1 in a family |
| Megacystis-microcolon-intestinal hypoperistalsis syndrome caused by a homozygous loss-of-function variant in MYH11 |
| Heterotaxia and situs inversus totalis associated with a homozygous WDR16 deletion |
| Familial idiopathic steroid-resistant nephrotic syndrome caused by COL4A3 mutations |
| Small cell lung cancer: somatic mutations in TP53, TP73 and RB1 |
| Clear cell sarcoma of the kidney due to consistent in-frame internal tandem duplications of BCOR |
| Fetal akinesia deformation sequence: homozygosity mapping in two fetuses revealed MUSK as a candidate gene |
| Language impairment, autism spectrum disorder and intellectual disability might be associated with ELP4 deletions |
| Keratoconus: WNT10A exonic variant increases the risk of disease |
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| Research in Action |
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| Clinical Research |
| Dravet syndrome: vaccination-associated seizure onset does not affect disease course, while the risk of subsequent vaccination associated seizures seems vaccine-specific |
| Progressive familial intrahepatic cholestasis type 2: improvement of cholestasis with 4-phenylbutyrate |
| Alpha-1-antitrypsin deficiency: purified α1 proteinase inhibitor augmentation treatment slows progression of emphysema |
| Recessive dystrophic epidermolysis bullosa: promising efficacy and tolerance with systemic allogeneic mesenchymal stromal cell therapy |
| Facioscapulohumeral dystrophy: regular aerobic training with or without post-exercise protein-carbohydrate supplementation improves fitness |
| Extranodal nasal NK/T cell lymphoma: Epstein-Barr virus latent membrane protein 1 and 2a transfer as a safe and effective post-remission therapy |
| Biliary tract cancer: cediranib in combination with cisplatin and gemcitabine does not improve the progression-free survival of patients |
| Paraganglioma in pregnancy: a case series and review of the literature |
| Salla disease: 13-year follow-up of Finnish patients |
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| Therapeutic Approaches |
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| Jervell and Lange-Nielsen syndrome: review on human induced pluripotent stem cell models |
| Huntington disease: fingolimod enhances hippocampal synaptic plasticity and memory in mice |
| Ebola hemorrhagic fever: aerosolized vaccine protects macaques exposed to the virus |
| Dystrophic epidermolysis bullosa: high local concentrations of intradermal mesenchymal stromal cells restore skin integrity and facilitate wound healing in a mouse model |
| Retinitis pigmentosa: ciliary neurotrophic factor gene therapy confers lifelong neuroprotection in a mouse model |
| Leber congenital amaurosis and retinitis pigmentosa: mitigated results with adeno-associated virus-mediated gene therapy in mouse models |
| Duchenne muscular dystrophy: galectin-1 protein therapy prevents pathology and improves muscle function in the mdx mouse model |
| Steinert myotonic dystrophy: recombinant adeno-associated viral vectors injected intravenously reduce disease pathology in muscles of mice |
| Fragile X-associated tremor/ataxia syndrome: new inducible mouse model |
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| Diagnostic Approaches |
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| Walker-Warburg syndrome: chromosomal microarray analysis as a first-line diagnostic test in patients with a fetus with one or more major structural abnormalities identified |
| Distinct optical coherence tomography patterns clearly differentiates Susac syndrome from relapsing-remitting multiple sclerosis |
| CARASIL: characteristic features and progression of abnormalities on magnetic resonance imaging |
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| Patient Management and Therapy |
| Cystic fibrosis: review on tiotropium bromide and tobramycin for the treatment |
| Fanconi anemia: review on gene therapy |
| Lymphangioleiomyomatosis: review on new treatments |
| Blepharospasm: review on alternatives to botulinum toxin for the management Id: |
| Congenital hyperinsulinism: review on molecular mechanisms, therapeutic targets and management |
| Kawasaki disease: a review |
| Paediatric rheumatology: review on lessons from oncology to optimize treatment |
| Metachromatic leukodystrophy: review on hematopoietic stem cell transplantation |
| B-cell non-Hodgkin lymphoma: review on the treatment |
| Huntington disease: a review |
| MECP2 disorders: a review |
| Glycogen storage disease due to acid maltase deficiency: a review |
| Congenital generalized lipodystrophies: a review |
| Ribosomopathies: a review |
| Duchenne muscular dystrophy: a review |
| Familial dilated cardiomyopathy: review on diagnosis, prevalence and screening |
| Tuberous sclerosis: review on pathophysiology |
| West-Nile encephalitis: a review |
| Idiopathic interstitial pneumonias with connective tissue diseases features: a review |
| Primary biliary cirrhosis and primary sclerosing cholangitis: a review |
| Eosinophilic esophagitis and gastroenteritis: a review |
| T-cell large granular lymphocyte leukemia: review on pathogenesis and treatment |
| One new and nine updated GeneReviews published |
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| Orphan Drugs |
| Analysing the ability of fulfilling the obligations of conditionally approved drugs in Europe |
| Wanted: new models of pricing and reimbursement for gene therapies |
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| Regulatory News |
| FDA approves new orphan drug to treat 20 patients worldwide |
| New treatment option for patients with multiple myeloma |
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| Grants |
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| Medical Research Grant Application Guidelines : Progeria Research Foundation |
| AFM Telethon: Call for proposals |
| Neuronal Ceroid Lipofuscinosis Research Award |
| BMBF Funding initiative: innovative stem cell technologies for personalized medicine |
| 8th Call for SMA research proposals |
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| Partnersearch, Job Opportunities |
| ECRIN ERIC job vacancies |
| Civil Society representatives: Call for expression of interest is open for the EMA Management Board |
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| Courses & Educational Initiatives |
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| The 2nd Biennial Australian Rare Lung Disease Short Course |
| Courses offered by Recordati Rare Diseases Foundation |
| EMA workshop on demonstrating significant benefit of orphan medicines |
| European Cytogenetesists Association |
| EMA workshop on pre-licencing activities |
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| What's on Where? |
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| CLIMB Newborn Screening Conference |
| Xth Annual ICORD Meeting, part of the Global Rare Diseases Week, Mexico |
| 6th South Eastern European Cystic Fibrosis Conference |
| NORD Summit |
| 13th Annual Congress Of International Drug Discovery Science & Technology, Therapy And Expo‐2015 |
| The BioData World Congress 2015 |
| 6th World Congress on Targeting Mitochondria |
| The AANEM Annual Meeting |
| 4th European Congress on Rett Syndrome |
| First European Congress on Hereditary ATTR amyloidosis ECATTR |
| 2nd International Primary Immunodeficiencies Congress (IPIC) |
| Sixth Croatian Congress of Human Genetics |
| 16th International Conference on Human Genome Variation and Complex Genome Analysis |
| Statistical analysis of massive genomic data |
| The Rett Syndrome Journey: Pathways to Follow |
| 6th European Symposium on rare anaemias - 1st Dutch-Belgian meeting for patients and health professionals |
| International Conference on Sanfilippo Syndrome and related Lysosmal Storage Diseases |
| Clinical trials in small populations : Methodological challenges and solutions |
| CDDF-SIOPE-ENCCA-ITCC 4th Paediatric Oncology Conference |
| CDDF-SIOPE-ENCCA-ITCC 4th Paediatric Oncology Conference |
| BPSU Rare Disease Conference 2016 |
| Clinical Innovation & Outsourcing |
| The RE(ACT) Congress |
| MYOLOGY 2016 Fifth International Congress of Myology |
| 13th International Congress of Human Genetics (ICHG) 2016 |
| 8th Alstrom Syndrome International Conference |
| 17th EMSOS Nurse and allied professional Group Meeting |
| European Association of Centres of Medical Ethics Conference |
| 9th ISNS International meeting/10th ISNS European Regional meeting |
| ESID European Society for Immunodeficiencies: Biennial meeting |
Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182,6932607174
Read More »
Brain Pathology
Florian Selt, Alica Deiß, Andrey Korshunov, David Capper, Hendrik Witt, Cornelis M. Van Tilburg, David T. W. Jones, Ruth Witt, Felix Sahm, David Reuss, Christian Kölsche, Jonas Ecker, Ina Oehme, Thomas Hielscher, Andreas Von Deimling, Andreas E. Kulozik, Stefan M. Pfister, Olaf Witt, Till Milde · Wednesday, October 07, 2015, 11:08
Abstract
The "Pediatric Targeted Therapy" (PTT) program aims to identify the presence and activity of druggable targets and evaluate the clinical benefit of a personalized treatment approach in relapsed or progressive tumors on an individual basis. 10 markers (HDAC2, HR23B, p-AKT, p-ERK, p-S6, p-EGFR, PDGFR-alpha/beta, p53, and BRAFV600E) were analyzed by immunohistochemistry. Pediatric patients with tumors independent of the histological diagnosis, with relapse or progression after treatment according to standard protocols were included. n=61/145 (42%) cases were elegible for analysis between 2009 and 2013, the most common entities being brain tumors. Immunohistochemical stainings were evaluated by the H-Score (0-300). In 93% of the cases potentially actionable targets were identified. The expressed or activated pathways were HDACs (83.0% of cases positive), EGFR (87.2%), PDGFR (75.9%), p53 (50.0%), MAPK/ERK (43.3%), and PI3K/mTOR (36.1%). Follow-up revealed partial or full implementation of PTT results in treatment decision making in 41% of the cases. Prolonged disease stabilization responses in single cases were noticed, however response rates did not differ from cases treated with other modalities. Further studies evaluating the feasibility and clinical benefit of personalized diagnostic approaches using paraffin material are warranted. This article is protected by copyright. All rights reserved.
Tags: Pathology
Ji Eun Oh, Takashi Ohta, Naosuke Nonoguchi, Kaishi Satomi, David Capper, Daniela Pierscianek, Ulrich Sure, Anne Vital, Werner Paulus, Michel Mittelbronn, Manila Antonelli, Paul Kleihues, Felice Giangaspero, Hiroko Ohgaki · Wednesday, October 07, 2015, 11:08
Abstract
The majority of glioblastomas develop rapidly with a short clinical history (primary glioblastoma IDH wild-type), whereas secondary glioblastomas progress from diffuse astrocytoma or anaplastic astrocytoma. IDH mutations are the genetic hallmark of secondary glioblastomas. Gliosarcomas and giant cell glioblastomas are rare histological glioblastoma variants, which usually develop rapidly. We determined the genetic patterns of 36 gliosarcomas and 19 giant cell glioblastomas. IDH1 and IDH2 mutations were absent in all 36 gliosarcomas and in 18 of 19 giant cell glioblastomas analyzed, indicating that they are histological variants of primary glioblastoma. Furthermore, LOH 10q (88%) and TERT promoter mutations (83%) were frequent in gliosarcomas. Copy number profiling using the 450k methylome array in 5 gliosarcomas revealed CDKN2Ahomozygous deletion (3 cases), trisomy chromosome 7 (2 cases), and monosomy chromosome 10 (2 cases). Giant cell glioblastomas had LOH 10q in 50% and LOH 19q in 42% of cases. ATRX loss was detected immunohistochemically in 19% of giant cell glioblastomas, but absent in 17 gliosarcomas. These and previous results suggest that gliosarcomas are a variant of, and genetically similar to, primary glioblastomas, except for a lack of EGFR amplification, while giant cell glioblastoma occupies a hybrid position between primary and secondary glioblastomas. This article is protected by copyright. All rights reserved.
Tags: Pathology
Jared Shows, Carrie Marshall, Arie Perry, B.k. Kleinschmidt-demasters · Wednesday, October 07, 2015, 11:08
Tags: Pathology
Chikako Ikeda, Osamu Yokota, Shigeto Nagao, Hideki Ishizu, Etsuko Oshima, Masato Hasegawa, Yuko Okahisa, Seishi Terada, Norihito Yamada · Tuesday, October 06, 2015, 15:08
Abstract
Progressive supranuclear palsy (PSP) cases frequently have argyrophilic grain disease (AGD). However, the PSP-like tau pathology in AGD cases has not been fully clarified. To address this, we examined tau pathologies in the subcortical nuclei and frontal cortex in 19 AGD cases that did not meet the pathological criteria of PSP or corticobasal degeneration, nine PSP cases, and 20 Braak NFT stage–matched controls. Of the 19 AGD cases, five (26.3%) had a few Gallyas-positive tau-positive tufted astrocytes (TAs) and Gallyas-negative tau-positive TA-like astrocytic inclusions (TAIs), and six (31.6%) had only TAIs in the striatum and/or frontal cortex. Subcortical tau pathology wassequentially and significantly greater in AGD cases lacking these tau-positive astrocytic lesions, AGD cases having them, and PSP cases than in controls. There was a significant correlation between three histologic factors, including the AGD stage and the quantities of subcortical neuronal and astrocytic tau pathologies. Tau immunoblotting demonstrated 68- and 64-kDa bands and 33-kDa low-molecular mass tau fragments in PSP cases, and although with lesser intensity, in AGD cases with and without TAs and TAIs also. Given these findings, the progression of AGD may be associated with development of the neuronal and astrocytic tau pathologies characteristic of PSP. This article is protected by copyright. All rights reserved.
Tags: Pathology
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Atlas of Thyroid CytoPathology,http://t.co/Wu5WKrTTuD
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Cephalalgia current issue
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Charles, A., 2015-10-07 07:57:34 AM
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Davenport, W. J., 2015-10-07 07:57:34 AM
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Ewering, C., Hasal, N., Alten, F., Clemens, C. R., Eter, N., Oberwahrenbrock, T., Kadas, E. M., Zimmermann, H., Brandt, A. U., Osada, N., Paul, F., Marziniak, M., 2015-10-07 07:57:34 AM
Background
The exact pathophysiology of cluster headache (CH) is still not fully clarified. Various studies confirmed changes in ocular blood flow during CH attacks. Furthermore, vasoconstricting medication influences blood supply to the eye. We investigated the retina of CH patients for structural retinal alterations with optical coherence tomography (OCT), and how these changes correlate to headache characteristics, oxygen use and impaired visual function.
Methods
Spectral domain OCT of 107 CH patients – 67 episodic, 35 chronic, five former chronic sufferers – were compared to OCT from 65 healthy individuals. Visual function tests with Sloan charts and a substantial ophthalmologic examination were engaged.
Results
Reduction of temporal and temporal-inferior retinal nerve fibre layer (RNFL) thickness was found in both eyes for CH patients with a predominant thinning on the headache side in the temporal-inferior area. Chronic CH patients revealed thinning of the macula compared to episodic suffers and healthy individuals. Bilateral thinning of temporal RNFL was also found in users of 100% oxygen compared to non-users and healthy controls. Visual function did not differ between patients and controls.
Discussion
Our OCT findings show a systemic effect causing temporal retinal thinning in both eyes of CH patients possibly due to attack-inherent or medication-induced frequent bilateral vessel diameter changes. The temporal retina with its thinly myelinated parvo-cellular axons and its more susceptible vessels for the vasoconstricting influence of oxygen inhalation seems to be predisposed for tissue damage-causing processes related to CH.
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Dilli, E., Halker, R., Vargas, B., Hentz, J., Radam, T., Rogers, R., Dodick, D., 2015-10-07 07:57:34 AM
Background
Occipital nerve (ON) injections with corticosteroids and/or local anesthetics have been employed for the acute and preventive treatment of migraine for decades. However, to date there is no randomized, placebo-controlled evidence to support the use of occipital nerve block (ONB) for the prevention of migraine.
Objective
The objective of this article is to determine the efficacy of ONB with local anesthetic and corticosteroid for the preventive treatment of migraine.
Participants and methods
Patients between 18 and 75 years old with ICHD-II-defined episodic (> 1 attack per week) or chronic migraine (modified ICHD-II as patients with > 10 days with consumption of acute medications were permitted into the study) were randomized to receive either 2.5 ml 0.5% bupivacaine plus 0.5 ml (20 mg) methylprednisolone over the ipsilateral (unilateral headache) or bilateral (bilateral headache) ON or 2.75 ml normal saline plus 0.25 ml 1% lidocaine without epinephrine (placebo). Patients completed a one-month headache diary prior to and after the double-blind injection. The primary outcome measure was defined as a 50% or greater reduction in the frequency of days with moderate or severe migraine headache in the four-week post-injection compared to the four-week pre-injection baseline period.
Results
Thirty-four patients received active and 35 patients received placebo treatment. Because of missing data, the full analysis of 33 patients in the active and 30 patients in the placebo group was analyzed for efficacy. In the active and placebo groups respectively, the mean frequency of at least moderate (mean 9.8 versus 9.5) and severe (3.6 versus 4.3) migraine days and acute medication days (7.9 versus 10.0) were not substantially different at baseline. The percentage of patients with at least a 50% reduction in the frequency of moderate or severe headache days was 30% for both groups (10/30 vs nine of 30, 0.00, 95% CI –0.22 to 0.23).
Conclusions
Greater ONB does not reduce the frequency of moderate to severe migraine days in patients with episodic or chronic migraine compared to placebo.
The study was registered with ClinicalTrial.gov (NCT00915473).
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Barloese, M., Lund, N., Petersen, A., Rasmussen, M., Jennum, P., Jensen, R., 2015-10-07 07:57:34 AM
Background and aim
Cluster headache (CH) is the headache disorder with the strongest chronobiological traits. The severe attacks of pain occur with diurnal and annual rhythmicity but the precise rhythm and involvement of potential zeitgebers is unknown. Patients complain of poor sleep quality yet this has never been studied. We investigated triggers, rhythms, sleep quality and chronotypes in CH.
Methods
Patients and controls completed questionnaires and structured interviews composed of new and previously validated parts including the Pittsburgh Sleep Quality Index (PSQI) and Morningness-Eveningness Questionnaire (MEQ). Patients were characterized by a CH index, a unified measure of headache burden.
Results
A total of 275 CH patients and 145 matched controls were included. The most common trigger was sleep (80%) and a relationship between clusters and daylight was identified. Of the patients, 82.2% reported diurnal and 56% annual rhythmicity. Patients reported impaired sleep quality (PSQI) (p < 0.0001) and an inverse relationship between time passed since last attack and sleep quality was identified (p < 0.0001). The CH index was positively related to the PSQI (p < 0.0001).
Conclusion
Diurnally, CH exhibits a relationship with night-time and annually with daylight hours. Patients' sleep quality is reduced compared with controls. Results suggest a complex relationship as sleep quality improves between clusters, but remains pathological.
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Vinogradova, L. V., 2015-10-07 07:57:34 AM
Background
Migraine and epilepsy are highly co-morbid neurological disorders associated with episodic dysfunction of both cortical and subcortical networks. The study examined the interrelation between cortical spreading depression, the electrophysiological correlate of migraine aura and seizures triggered at cortical and brainstem levels by repeated sound stimulation in rats with acoustic hypersensitivity (reflex audiogenic epilepsy).
Method
In awake, freely moving rats with innate audiogenic epilepsy, 25 episodes of running seizure (brainstem seizures) were induced by repeated sound stimulation. Spreading depression and seizures were recorded using implanted cortical electrodes.
Results
The first sound-induced brainstem seizures evoked neither spreading depression nor seizures in the cortex. With repetition, brainstem seizures began to be followed by a single cortical spreading depression wave and an epileptiform discharge. Spreading depression was more frequent an early cortical event than seizures: spreading depression appeared after 8.4 ± 1.0 repeated stimulations in 100% rats (n = 24) while cortical seizures were recorded after 12.9 ± 1.2 tests in 46% rats. Brainstem seizure triggered unilateral long-latency spreading depression. Bilateral short-latency cortical spreading depression was recorded only after intense cortical seizures.
Conclusion
These data show that episodic brainstem activation is a potent trigger of unilateral cortical spreading depression. Development of intense seizures in the cortex leads to initiation of spreading depression in multiple cortical sites of both hemispheres.
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Hagen, K., Brenner, E., Linde, M., Gravdahl, G. B., Tronvik, E. A., Engstrom, M., Sonnewald, U., Helde, G., Stovner, L. J., Sand, T., 2015-10-07 07:57:34 AM
Background
Preventive medication is indicated for many migraine patients, but is used in relatively few. The aim of the present study was to evaluate the efficacy of acetyl-l-carnitine as a prophylactic drug in migraine patients.
Methods
A single-center, randomized, triple-blind, placebo-controlled, crossover study was carried out. Men and women, age 18–65 years, with episodic migraine but otherwise healthy, were recruited mostly through advertisements. After a four-week run-in-phase, 72 participants were randomized to receive either placebo or 3 g acetyl-l-carnitine for 12 weeks. After a four-week washout, treatment was switched. The primary outcome was days with moderate or severe headache per four weeks. Secondary outcomes were days with headache, hours with headache, proportion of responders (>50% reduction in migraine days from baseline) and adverse events.
Results
In the complete case analyses, no statistically significant differences were found between acetyl-l-carnitine and placebo in severe or moderate headache days per month (3.0 versus 3.1, p = 0.80), headache days per month (5.1 versus 5.2, p = 0.73) or for the other secondary outcome measures.
Conclusion
In this triple-blind crossover study no differences were found in headache outcomes between acetyl-l-carnitine and placebo. Our results do not provide evidence of benefit for efficacy of acetyl-l-carnitine as prophylactic treatment for migraine.
Trial registration: EUDRACT (2012-001624-36), ClinicalTrials.gov (NCT01695317).
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Woldeamanuel, Y., Rapoport, A., Cowan, R., 2015-10-07 07:57:34 AM
Background and objectives
Headaches recur in up to 87% of migraine patients visiting the emergency department (ED), making ED recidivism a management challenge. We aimed herein to determine the role of corticosteroids in the acute management of migraine in the ED and outpatient care.
Methods
Advanced search strategies employing PubMed/MEDLINE, Web of Science, and Cochrane Library databases inclusive of a relevant gray literature search was employed for Clinical Studies and Systematic Reviews by combining the terms "migraine" and "corticosteroids" spanning all previous years since the production of synthetic corticosteroids ca. 1950 until August 30, 2014. Methods were in accordance with MOOSE guidelines.
Results
Twenty-five studies (n = 3989, median age 37.5 years, interquartile range or IQR 35–41 years; median male:female ratio 1:4.23, IQR 1:2.1–6.14; 52% ED-based, 56% randomized-controlled) and four systematic reviews were included. International Classification of Headache Disorders criteria were applied in 64%. Nineteen studies (76%) indicated observed outcome differences favoring benefits of corticosteroids, while six (24%) studies indicated non-inferior outcomes for corticosteroids. Median absolute risk reduction was 30% (range 6%–48.2%), and 11% (6%–48.6%) for 24-, and 72-hour headache recurrence, respectively. Parenteral dexamethasone was the most commonly (56%) administered steroid, at a median single dose of 10 mg (range 4–24 mg). All meta-analyses revealed efficacy of adjuvant corticosteroids to various abortive medications—indicating generalizability. Adverse effects were tolerable. Higher disability, status migrainosus, incomplete pain relief, and previous history of headache recurrence predicted outcome favorability.
Conclusions
Our literature review suggests that with corticosteroid treatment, recurrent headaches become milder than pretreated headaches and later respond to nonsteroidal therapy. Single-dose intravenous dexamethasone is a reasonable option for managing resistant, severe, or prolonged migraine attacks.
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Bridge, H., Stagg, C. J., Near, J., Lau, C.-i., Zisner, A., Cader, M. Z., 2015-10-07 07:57:34 AM
Background
Visual aura is present in about one-third of migraine patients and triggering by bright or flickering lights is frequently reported.
Method
Using migraine with visual aura patients, we investigated the neurochemical profile of the visual cortex using magnetic resonance spectroscopy. Specifically, glutamate/creatine and GABA/creatine ratios were quantified in the occipital cortex of female migraine patients.
Results
GABA levels in the occipital cortex of migraine patients were lower than that of controls. Glutamate levels in migraine patients, but not controls, correlated with the blood-oxygenation-level-dependent (BOLD) signal in the primary visual cortex during visual stimulation.
Conclusion
Migraine with visual aura appears to disrupt the excitation-inhibition coupling in the occipital cortex.
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Sanchez-Montanez, A., Morana, G., Mancardi, M. M., Janis, S., Severino, M., Verrina, E., Rossi, A., 2015-10-07 07:57:34 AM
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Dilli, E., Dodick, D. W., 2015-10-07 07:57:34 AM
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Charleston, L., 2015-10-07 07:57:34 AM
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2015-10-07 07:57:34 AM
Stefan Seidel, Andreas Böck, Werner Schlegel, Arzu Kilic, Gudrun Wagner, Gloria Gelbmann, Almut Hübenthal, Incifer Kanbur, Sofia Natriashvili, Andreas Karwautz, Christian Wöber and iek Wöber-Bingöl. Increased RLS prevalence in children and adolescents with migraine: A case-control study. Cephalalgia 2012; 32: 693–699. DOI:10.1177/0333102412446207.
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Diagnostic Terminology and Criteria for The Cytologic Diagnosis of THYROID LESIONS,
Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182,6932607174
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The Journal of Headache and Pain
Elevated blood pressure and headache disorders in China – associations, under-treatment and implications for public health
Background: Both hypertension (HTN) and headache disorders are highly prevalent worldwide. Our purpose, in a nationwide study of the Chinese general population, was to evaluate any association between primary headache disorders and elevated blood pressure (eBP). We could not collect data on antihypertensive therapy, but took the view that, whatever such therapy might be taken, eBP was a sign that it was failing to meet treatment needs. Therefore, as a secondary purpose, important from the public-health perspective, we would present the prevalence of eBP (treated or not) as indicative of unmet health-care need in China. Methods: This was a questionnaire-based nationwide cross-sectional door-to-door survey using cluster random-sampling, selecting one adult (18–65 years) per household. Headache was diagnosed by ICHD-II criteria and eBP as systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg. Chi-squared test and multivariate logistic regression analysis were used to assess the strength and significance of associations. We set significance at P ≤ 0.05. Results: Of 5,041 survey participants (participation rate 94.1 %), 154 were excluded because of missing BP data, leaving 4,987 for analysis [mean age: 43.6 ± 12.8 years; male 2,532 (mean age: 43.4 ± 12.9 years); female 2,455 (mean age 43.9 ± 12.8 years)]. There were 466 participants with migraine, 535 with tension type headache (TTH) and 48 with all causes of headache on ≥15 days/month. The prevalence of eBP was 22.1 % (males 22.9 %, females 21.3 %). No associations of eBP with any of the headache disorders survived multivariate adjusted analysis. The demographic and anthropometric variables most strongly associated with eBP were higher age (AOR 3.7) and being overweight (AOR 2.4), seen in both genders. Less strong were male gender, lower educational level and urban habitation. Conclusions: We found no clear-cut associations between eBP and any headache disorder. The associations with demographic and anthropometric variables may have acted as confounders in past reports to the contrary. We did find an alarmingly high prevalence of eBP, recognizing that this signals substantial under-treatment in China of a serious condition, and therefore a major public-health concern. |
Prevalence of primary headache disorders in Fayoum Governorate, Egypt
Background: There is abundance of epidemiological studies of headache in developed and western countries; however, data in developing countries and in Egypt are still lacking. This study aims to detect the prevalence of primary headache disorders in both urban and rural sectors in Fayoum governorate, Egypt. Methods: A total of 2600 subjects were included using multi-stage stratified systematic random sampling, with respondent rate of 91.3 %. A pre-designed Arabic version, interviewer-administered, pilot tested structured questionnaire was developed according to The International Classification of Headache Disorders, 3rd edition (beta version), and this questionnaire was validated and the strength of agreement in headache diagnosis was good. Results: The 1-year headache prevalence was 51.4 %, which was more prevalent in urban dwellers. The most common primary headache type was episodic tension type headache (prevalence; 24.5 %), followed by episodic migraine (prevalence; 17.3 %), both types peaked in midlife. Headache disorders were more common in females with exception of cluster headache that showed the expected male dominance. The risk of chronic headache increased more than one fold and half when the participants were females, married, and in those with high education. More than 60 % of our participants did not seek medical advice for their headaches problem; this percentage was higher in rural areas. Conclusions: Primary headache disorders are common in Egypt; prevalence rate was comparable with western countries with exception of episodic tension headache. Still headache is under-estimated and under-recognized in Egypt and this problem should be targeted by health care providers. |
Thermal and mechanical quantitative sensory testing in chinese patients with burning mouth syndrome – a probable neuropathic pain condition?
Background: To explore the hypothesis that burning mouth syndrome (BMS) probably is a neuropathic pain condition, thermal and mechanical sensory and pain thresholds were tested and compared with age- and gender-matched control participants using a standardized battery of psychophysical techniques. Methods: Twenty-five BMS patients (men: 8, women: 17, age: 49.5 ± 11.4 years) and 19 age- and gender-matched healthy control participants were included. The cold detection threshold (CDT), warm detection threshold (WDT), cold pain threshold (CPT), heat pain threshold (HPT), mechanical detection threshold (MDT) and mechanical pain threshold (MPT), in accordance with the German Network of Neuropathic Pain guidelines, were measured at the following four sites: the dorsum of the left hand (hand), the skin at the mental foramen (chin), on the tip of the tongue (tongue), and the mucosa of the lower lip (lip). Statistical analysis was performed using ANOVA with repeated measures to compare the means within and between groups. Furthermore, Z-score profiles were generated, and exploratory correlation analyses between QST and clinical variables were performed. Two-tailed tests with a significance level of 5 % were used throughout. Results: CDTs (P < 0.02) were significantly lower (less sensitivity) and HPTs (P < 0.001) were significantly higher (less sensitivity) at the tongue and lip in BMS patients compared to control participants. WDT (P = 0.007) was also significantly higher at the tongue in BMS patients compared to control subjects . There were no significant differences in MDT and MPT between the BMS patients and healthy subjects at any of the four test sites. Z-scores showed that significant loss of function can be identified for CDT (Z-scores = −0.9±1.1) and HPT (Z-scores = 1.5±0.4). There were no significant correlations between QST and clinical variables (pain intensity, duration, depressions scores). Conclusion: BMS patients had a significant loss of thermal function but not mechanical function, supporting the hypothesis that BMS may be a probable neuropathic pain condition. Further studies including e.g. electrophysiological or imaging techniques are needed to clarify the underlying mechanisms of BMS. |
Clinical and Demographical Characteristics of Patients with Medication Overuse Headache in Argentina and Chile: Analysis of the Latin American Section of COMOESTAS Project
Background: Data on the characteristics of Medication Overuse Headache (MOH) in Latin American (LA) are scarce. Here we report the demographic and clinical features of the MOH patients from Argentina and Chile enrolled in the multinational COMOESTAS project in the period 2008–2010. Methods: The LA population was formed by 240 MOH subjects, 110 from Chile and 130 from Argentina, consecutively attending the local headache centres. In each centre, specifically trained neurologist interviewed and confirmed the diagnosis according to the ICHD-II criteria. A detailed history was collected on an electronic patient record form. Results: The mean patient age was 38.6 years, with a female/male ratio of 8:2. The mean time since onset of the primary headache was 21 years, whereas duration of MOH was 3.9 years. The primary headache was migraine without aura in 77.5 % and migraine with aura in 18.8 %. Forty two % of the patients self-reported emotional stress associated with the chronification of headache; 43.8 % reported insomnia. The most overused medications were acute drug combinations containing ergotamine (70 %), NSAIDs (33.8 %) and triptans (5.4 %). Conclusion: Though little described, MOH is present also in LA, where it affects mostly women, in the most active decades of life. Some differences emerge as regards the demographic and clinical characteristics of MOH in this population as compared to Europe or Northern America. What seems more worrying about MOH in Argentina and Chile is that most patients overuse ergotamine, a drug that may cause serious adverse events when used chronically. These findings once more underscore the importance of properly diagnose and treat MOH. |
Responsiveness of the autonomic nervous system during paced breathing and mental stress in migraine patients
Background: Migraine is a stress-related disorder, suggesting that there may be sympathetic hyperactivity in migraine patients. However, there are contradictory results concerning general sympathetic activation in migraine patients. To shed more light on the involvement of the autonomic nervous system (ANS) in migraine pathophysiology, we investigated cardiac and cardiovascular reactions during vagal (paced breathing) and sympathetic activation (mental stress test). Methods: Heart rate variability parameters and skin conductance responses were recorded interictally in 22 episodic migraine patients without aura and 25 matched controls during two different test conditions. The paced breathing test consisted of a five-minute baseline, followed by two minutes of paced breathing (6 breathing cycles per minute) and a five-minute recovery phase. The mental stress test consisted of a five-minute baseline, followed by one minute of stress anticipation, three and a half minutes of mental stress and a five-minute recovery phase. Furthermore we measured blood pressure and heart rate once daily over 2 weeks. Subjects rated their individual current stress level and their stress level during paced breathing and during the mental stress test. Results: There were no significant differences between migraine patients and controls in any of the heart rate variability parameters in either time domain or frequency domain analysis. However, all parameters showed a non-significant tendency for larger sympathetic activation in migraine patients. Also, no significant differences could be observed in skin conductance responses and average blood pressure. Only heart rates during the 2-week period and stress ratings showed significantly higher values in migraine patients compared to controls. Conclusions: Generally there were no significant differences between migraine patients and controls concerning the measured autonomic parameters. There was a slight but not significant tendency in the migraine patients to react with less vagal and more sympathetic activation in all these tests, indicating a slightly changed set point of the autonomic system. Heart rate variability and blood pressure in migraine patients should be investigated for longer periods and during more demanding sympathetic activation. |
Comparison of tolerability and adverse symptoms in oxcarbazepine and carbamazepine in the treatment of trigeminal neuralgia and neuralgiform headaches using the Liverpool Adverse Events Profile (AEP)
Background: Adverse effects of drugs are poorly reported in the literature . The aim of this study was to examine the frequency of the adverse events of antiepileptic drugs (AEDs), in particular carbamazepine (CBZ) and oxcarbazepine (OXC) in patients with neuralgiform pain using the psychometrically tested Liverpool Adverse Events Profile (AEP) and provide clinicians with guidance as to when to change management. Methods: The study was conducted as a clinical prospective observational exploratory survey of 161 patients with idiopathic trigeminal neuralgia and its variants of whom 79 were on montherapy who attended a specialist clinic in a London teaching hospital over a period of 2 years. At each consultation they completed the AEP questionnaire which provides scores of 19–76 with toxic levels being considered as scores >45. Results: The most common significant side effects were: tiredness 31.3 %, sleepiness 18.2 %, memory problems 22.7 %, disturbed sleep 14.1 %, difficulty concentrating and unsteadiness 11.6 %. Females reported significantly more side effects than males. Potential toxic dose for females is approximately 1200 mg of OXC and 800 mg of CBZ and1800mg of OXC and 1200 mg of CBZ for males. Conclusions: CBZ and OXC are associated with cognitive impairment. Pharmacokinetic and pharmacodynamic differences are likely to be the reason for gender differences in reporting side effects. Potentially, females need to be prescribed lower dosages in view of their tendency to reach toxic levels at lower dosages.Side effects associated with AED could be a major reason for changing drugs or to consider a referral for surgical management. |
Neck pain in episodic migraine: premonitory symptom or part of the attack?
Background: Whether neck pain (NP) is a prodromal migraine symptom or belongs to the migraine attack feature remains controversial. Methods: In order to prospectively record neck pain (NP) and non-headache symptoms and to evaluate the percentage of patients having NP as clear premonitory, non-headache symptom of their migraine, a specific self fulfilled questionnaire was designed to record NP and premonitory symptoms in a migraine cohort. All patients who reported NP anytime during the migraine phase were allocated to 3 groups: A = NP starts with the onset of headache; B = NP starts < 2 h before the onset of headache; C = NP starts 2-48 h before the onset of headache. Results: Data were evaluated from 487 migraineurs with episodic migraine (73.1 % females; 77 % had migraine without aura). 338 patients (69.4 %) reported NP anytime during the migraine phase. 184 patients (group A; 54.4 %) noticed NP with the start of the headache phase; 118 patients (group B; 24.2 %) reported NP within 2 h before the headache phase; 36 patients (group C; 7.4 %) experienced NP 2-48 h before the headache phase. In group B we found a high proportion of typical migraine associated symptoms and NP progressed into the headache phase in 82.2 %. Conclusions: These data indicate that NP is a very common feature of migraine attacks and is more likely to be part of the migraine attack than a prodromal migraine symptom. |
Dural administration of inflammatory soup or Complete Freund's Adjuvant induces activation and inflammatory response in the rat trigeminal ganglion
Background: Migraine is a painful disorder with a huge impact on individual and public health. We hypothesize that migraine pain originates from a central mechanism that results secondarily in hypersensitivity in peripheral afferents associated with the cerebral and cranial blood vessels. It has previously been shown that application of inflammatory or algesic substances onto the dura mater or chemical stimulation of the dural receptive fields causes hypersensitivity to mechanical and thermal stimulation together with direct activation of the TG. We asked whether local inflammation of dura mater induces inflammatory activation in the trigeminal ganglion. Methods: We performed topical administration of inflammatory soup (IS) or Complete Freund's Adjuvant (CFA) onto an exposed area of the rat dura mater in vivo for 20 min. The window was closed and the rats were sacrificed after 4 h and up to 7 days. Myography was performed on middle meningeal arteries. The trigeminal ganglia were removed and processed for immunohistochemistry or Western blot. Results: Both CFA and IS induced enhanced expression of pERK1/2, IL-1β and CGRP in the trigeminal ganglia. The pERK1/2 immunoreactivity was mainly seen in the satellite glial cells, while IL-1β reactivity was observed in the neuronal cytoplasm, close to the cell membrane, seemingly as sign of neuro-glial interaction. The CGRP expression in the neurons and nerve fibres was enhanced after the application of either inflammatory agent. Myography resulted in a strong vasoconstrictor response to IS, but not to CFA. Conclusions: These results suggest that the application of IS or CFA onto the dura mater causes long-term activation of the TG and demonstrate the importance of the neuro-glial interaction in the activation of the trigeminovascular system. |
Neurobiology and sleep disorders in cluster headache
Cluster headache is characterized by unilateral attacks of severe pain accompanied by cranial autonomic features. Apart from these there are also sleep-related complaints and strong chronobiological features. The interaction between sleep and headache is complex at any level and evidence suggests that it may be of critical importance in our understanding of primary headache disorders. In cluster headache several interactions between sleep and the severe pain attacks have already been proposed. Supported by endocrinological and radiological findings as well as the chronobiological features, predominant theories revolve around central pathology of the hypothalamus. We aimed to investigate the clinical presentation of chronobiological features, the presence of concurrent sleep disorders and the relationship with particular sleep phases or phenomena, the possible role of hypocretin as well as the possible involvement of cardiac autonomic control. We conducted a questionnaire survey on 275 cluster headache patients and 145 controls as well an in-patient sleep study including 40 CH-patients and 25 healthy controls. The findings include: A distinct circannual connection between cluster occurrence and the amount of daylight, substantially poorer sleep quality in patients compared to controls which was present not only inside the clusters but also outside, affected REM-sleep in patients without a particular temporal connection to nocturnal attacks, equal prevalence of sleep apnea in both patient and control groups, reduced levels of hypocretin-1 in the cerebrospinal fluid of patients and finally a blunted response to the change from supine to tilted position in the head-up tilt table test indicating a weakened sympathoexcitatory or stronger parasympathetic drive. Overall, these findings support a theory of involvement of dysregulation in hypothalamic and brainstem nuclei in cluster headache pathology. Further, it is made plausible that the headache attacks are but one aspect of a more complex syndrome of central dysregulation manifesting as sleep-related complaints, sub-clinical autonomic dysregulation and of course the severe attacks of unilateral headache. Future endeavors should focus on pathological changes which persist in the attack-free periods but also heed the possibility of long-lived, cluster-induced pathology. |
Validation of potential candidate biomarkers of drug-induced nephrotoxicity and allodynia in medication-overuse headache
Background: Medication-overuse headache (MOH) is a chronic disorder that results from the overuse of analgesics drugs, triptans or other acute headache compounds. Although the exact mechanisms underlying MOH remain still unknown, several studies suggest that it may be associated with development of "central sensitization", which may cause cutaneous allodynia (CA). Furthermore, the epidemiology of drug-induced disorders suggests that medication overuse could lead to nephrotoxicity. The aim of this work was to confirm and validate the results obtained from previous proteomics studies, in which we analyzed the urinary proteome of MOH patients in comparison with healthy non-abusers individuals. Methods: MOH patients were divided into groups on the basis of the drug abused: triptans, non-steroidal anti-inflammatory drugs (NSAIDs) and mixtures, (mainly containing indomethacin, paracetamol and, in some cases, caffeine). Healthy subjects, with a history of normal renal function, were used as controls. In this study, four proteins that were found differentially expressed in urine, and, on the basis of the literature review, resulted related to kidney diseases, were verified by Western Blot and Enzyme-linked Immunosorbent Assay (ELISA); Prostaglandin-H2 D-synthase (PTGDS), uromodulin (UROM), alpha-1-microglobulin (AMBP) and cystatin-C (CYSC). Results: Western blot analysis allowed to validate our previous proteomics data, confirming that all MOH patients groups show a significant over-excretion of urinary PTGDS, UROM, AMBP and CYSC (excluding triptans group for this latter), in comparison with controls. Moreover, the expression of PTGDS was further evaluated by ELISA. Also by this assay, a significant increase of PTGDS was observed in all MOH abusers, according to 2-DE and Western blot results. Conclusions: In this study, we confirmed previous findings concerning urinary proteins alterations in MOH patients, identified and demonstrated the over-expression of PTGDS, UROM, AMBP, and CYSC, particularly in NSAIDs and mixtures abusers. Over-expression of these proteins have been related to renal dysfunction and probably, PTGDS, to the development of CA. The detection and confirmation of this proteins pattern represent a promising tool for a better understanding of potential nephrotoxicity induced by drugs overuse and may enhance awareness related to the MOH-associated risks, even in absence of clinical symptoms. |
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Alexandros Sfakianakis
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Cephalalgia -- Preview Articles
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Rapoport, A., Ravishankar, K., 2015-09-30 06:50:45 AM
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Petrusic, I., Podgorac, A., Zidverc-Trajkovic, J., Radojicic, A., Jovanovic, Z., Sternic, N., 2015-09-30 06:50:45 AM
Introduction
The aim of this study was to evaluate the prevalence and clinical impact of interictal microembolic signals (MES) in patients suffering from migraine with higher cortical dysfunction (HCD), such as language and memory impairment, during an aura.
Patients and methods
This study was carried out on 34 migraineurs with language and memory impairment during aura (HCD group), 31 migraineurs with only visual or visual and somatosensory symptoms during aura (Control group I), and 34 healthy controls (Control group II). We used a Doppler instrument to detect microemboli. Demographic data, disease features and the detection of MES between these groups, as well as the predictors of HCD during the aura, were analyzed.
Results
The duration of aura was longer and the frequency of aura was higher among patients with language and memory impairment during aura compared to Control group I. MES was detected in 29.4% patients from the HCD group, which was significantly higher compared to 3.2% in Control group I and 5.9% in Control group II. Regarding the absence or presence of MES, demographic and aura features were not different in the HCD subgroups. A longer duration of aura, the presence of somatosensory symptoms during the aura and the presence of interictal MES were independent predictors of HCD during the aura.
Conclusion
The present findings indicate that HCD and MES are related in patients with migraine with aura. Further research is needed to better understand the exact pathophysiological mechanism.
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Diener, H.-C., 2015-09-30 06:50:45 AM
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Gonzalez-Quintanilla, V., Toriello, M., Palacio, E., Gonzalez-Gay, M. A., Castillo, J., Montes, S., Martinez-Nieto, R., Fernandez, J., Rojo, A., Gutierrez, S., Pons, E., Oterino, A., 2015-09-30 06:50:45 AM
Background and objective
Unlike migraine and migraine with aura, little information exists regarding chronic migraine (CM) as a risk factor for cardiovascular disease. In this study we aim to determine whether an association between CM and endothelial dysfunction exists.
Methods
Individuals 18 years and older diagnosed with episodic migraine (EM) and CM according to ICHD criteria were studied. After an overnight fast and abstinence from vasoactive drugs, ultrasound studies were performed and blood samples taken from patients and matched controls according to internationally agreed on protocols.
Results
A total of 113 individuals were enrolled (35 CM, 37 EM, 41 controls). CM patients had a lower percentage of flow-mediated vasodilation (FMD; difference of means = 5.03%; p = 1.0E-6) and breath-holding index (BHI; difference of means 0.754; p = 2.0E-6), as well as increased carotid intima media thickness (cIMT; difference of means = 0.128 mm; p = 7.0E-5) than controls. The EM patients and controls comparison found similar, but less pronounced, differences: decreased BHI (p = 0.031), and increased cIMT (p = 0.028). Fibrinogen (r = 0.277; p = 0.006), C-reactive protein (r = 0.288; p = 0.003), and erythrocyte rate sedimentation (r = 0.298; p = 0.002) also correlated with cIMT, and inversely with BHImV and FMD.
Conclusions
Migraine is associated with systemic and cerebral endothelial dysfunction demonstrated by ultrasound studies and biological markers. The degree of these changes was strongly associated with the severity of migraine. Our data indicate that migraine may be a cerebral disorder with systemic endothelial damage.
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de Coo, I., Wilbrink, L., Haan, J., Ferrari, M., Terwindt, G., 2015-09-30 06:50:45 AM
Aim
In the revised criteria of the International Classification of Headache Disorders (ICHD-III beta) the following items are added to the diagnostic criteria of cluster headache: ipsilateral sensation of fullness in the ear and ipsilateral forehead/facial flushing. We evaluated the possible additional value of these symptoms for diagnosing cluster headache.
Methods
In this cross-sectional cohort study of (potential) cluster headache patients we investigated these additional symptoms using a Web-based questionnaire. Patients not fulfilling the ICHD-II criteria for cluster headache but fulfilling the ICHD-III beta criteria were interviewed.
Results
Response rate was 916/1138 (80.5%). Of all 573 patients with cluster headache according to ICHD-II criteria, 192 (33.5%) reported ipsilateral ear fullness and 113 (19.7%) facial flushing during attacks. There was no difference in reporting ipsilateral ear fullness and facial flushing between patients who received a diagnosis of cluster headache and patients who did not. None of the patients who did not fulfill all ICHD-II criteria could be categorized as cluster headache according to the ICHD-III beta criteria.
Conclusion
The results of this study do not support the addition of ear fullness and facial flushing to the new ICHD-III beta criteria.
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Gaul, C., Diener, H.-C., Silver, N., Magis, D., Reuter, U., Andersson, A., Liebler, E. J., Straube, A., on behalf of the PREVA Study Group, 2015-09-30 06:50:45 AM
Background
Chronic cluster headache (CH) is a debilitating disorder for which few well-controlled studies demon.strate effectiveness of available therapies. Non-invasive vagus nerve stimulation (nVNS) was examined as adjunctive prophylactic treatment of chronic CH.
Methods
PREVA was a prospective, open-label, randomised study that compared adjunctive prophylactic nVNS (n = 48) with standard of care (SoC) alone (control (n = 49)). A two-week baseline phase was followed by a four-week randomised phase (SoC plus nVNS vs control) and a four-week extension phase (SoC plus nVNS). The primary end point was the reduction in the mean number of CH attacks per week. Response rate, abortive medication use and safety/tolerability were also assessed.
Results
During the randomised phase, individuals in the intent-to-treat population treated with SoC plus nVNS (n = 45) had a significantly greater reduction in the number of attacks per week vs controls (n = 48) (–5.9 vs –2.1, respectively) for a mean therapeutic gain of 3.9 fewer attacks per week (95% CI: 0.5, 7.2; p = 0.02). Higher ≥50% response rates were also observed with SoC plus nVNS (40% (18/45)) vs controls (8.3% (4/48); p < 0.001). No serious treatment-related adverse events occurred.
Conclusion
Adjunctive prophylactic nVNS is a well-tolerated novel treatment for chronic CH, offering clinical benefits beyond those with SoC.
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Shin, R. K., Mejico, L. J., Boghen, D., 2015-09-30 06:50:45 AM
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Chong, C. D., Starling, A. J., Schwedt, T. J., 2015-09-30 06:50:45 AM
Background
Migraine attacks manifest with hypersensitivities to light, sound, touch and odor. Some people with migraine have photosensitivity between migraine attacks, suggesting persistent alterations in the integrity of brain regions that process light. Although functional neuroimaging studies have shown visual stimulus induced "hyperactivation" of visual cortex regions in migraineurs between attacks, whether photosensitivity is associated with alterations in brain structure is unknown.
Methods
Levels of photosensitivity were evaluated using the Photosensitivity Assessment Questionnaire in 48 interictal migraineurs and 48 healthy controls. Vertex-by-vertex measurements of cortical thickness were assessed in 28 people with episodic migraine who had interictal photosensitivity (mean age = 35.0 years, SD = 12.1) and 20 episodic migraine patients without symptoms of interictal photosensitivity (mean age = 36.0 years, SD = 11.4) using a general linear model design.
Results
Migraineurs have greater levels of interictal photosensitivity relative to healthy controls. Relative to migraineurs without interictal photosensitivity, migraineurs with interictal photosensitivity have thicker cortex in several brain areas including the right lingual, isthmus cingulate and pericalcarine regions, and the left precentral, postcentral and supramarginal regions.
Conclusion
Episodic migraineurs with interictal photosensitivity have greater cortical thickness in the right parietal-occipital and left fronto-parietal regions, suggesting that persistent light sensitivity is associated with underlying structural alterations.
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Raucci, U., Vanacore, N., Paolino, M. C., Silenzi, R., Mariani, R., Urbano, A., Reale, A., Villa, M. P., Parisi, P., 2015-09-30 06:50:45 AM
Background
Vertigo/Dizziness in childhood is not a rare cause of visits to the emergency department (ED). We analyzed a selected group with vertigo/dizziness to identify signs and symptoms that may help to guide the diagnostic approach and management.
Methods
A total of 616 children admitted for vertigo to the ED over a five-year period were retrospectively reviewed. Their medical history, clinical characteristics, laboratory and neuroimaging tests, final diagnoses and management were analyzed.
Results
Migraine and syncope were the most frequent causes. Two patients were affected by life-threatening cardiac syncope, while structural life-threatening central nervous system diseases were found in 15 patients, none of whom presented with vertigo as an isolated clinical finding.
Conclusions
Most cases of vertigo/dizziness in childhood that consist mainly of migraine and syncope are of benign origin. The prompt identification of neurological or cardiological signs or symptoms associated with vertigo in children is mandatory to rule out life-threatening conditions.
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Gil-Gouveia, R., Oliveira, A. G., Martins, I. P., 2015-09-30 06:50:45 AM
Background
The socio-economic impact of migraine is mostly related to work loss either by absenteeism or decreased work performance. Migraine-associated cognitive dysfunction during an attack may contribute to these difficulties.
Objective
The objective of this article is to analyze the presence and relevance of cognitive symptoms during migraine attacks and to relate their intensity and symptom-related disability with other migraine-defining symptoms.
Methods
Consecutive migraine patients of a headache clinic completed diaries scoring each migraine symptom (including cognitive symptoms) intensity and symptom-related disability.
Results
Of 100 consecutive patients included in this study, 34 (all females, age average 31.8 ± 8.8 years) returned information on 229 attacks, on average 6.7 per participant. Every symptom's intensity was always rated slightly higher than the disability it caused. Pain was the symptom scored with the highest intensity and disability, followed by cognitive symptoms (difficulty in thinking and worsening with mental effort) and photo- and phonophobia. Scoring was independent of any of the clinical variables. Attack intensity and disability scores correlated with intensity and disability from pain and from worsening with mental effort.
Conclusions
Attack-related cognitive symptoms are intense and disabling. Some attack-related cognitive symptoms correlate to intensity and disability subjectively attributed to the migraine attack. Cognitive performance should be addressed as a valuable secondary endpoint in trials of acute migraine treatment.
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Matosevic, B., Prieschl, M., Luef, G., Knoflach, M., Schmidauer, C., Willeit, J., Lackner, P., 2015-09-30 06:50:45 AM
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Schievink, W. I., Maya, M. M., 2015-09-30 06:50:45 AM
Background
Spontaneous intracranial hypotension due to a spinal cerebrospinal fluid (CSF) leak has become a well-recognized cause of headaches. Recently, various unusual neurological syndromes have been described in such patients with chronic ventral CSF leaks, including superficial siderosis and an amyotrophic lateral sclerosis-like syndrome. The authors now report two patients with spontaneous intracranial hypotension due to a chronic ventral CSF leak who suffered a diffuse non-aneurysmal subarachnoid hemorrhage (SAH).
Description of cases
A 62-year-old woman underwent uneventful microsurgical repair of a ventral thoracic CSF leak that had been present for 13 years. Seventeen months after surgery, she was found unresponsive and CT showed a diffuse intracranial SAH. Cerebral angiography and spine and brain MRI did not reveal a source of the SAH. A 73-year-old woman was found unresponsive and CT showed a diffuse intracranial SAH. Cerebral angiography and brain MRI did not reveal a source of the SAH, although superficial siderosis was detected. Spine MRI showed a ventral thoracic CSF leak that by history had been present for 41 years. She underwent uneventful microsurgical repair of the CSF leak.
Discussion
The authors suggest that patients with a ventral spinal CSF leak of long duration may be at risk of diffuse non-aneurysmal SAH.
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Tarasco, V., Grasso, G., Versace, A., Castagno, E., Ricceri, F., Urbino, A., Pagliero, R., 2015-09-30 06:50:45 AM
Aim
The aim of this article is to analyze the epidemiological and clinical features of migraine in a pediatric headache center.
Methods
A retrospective study was performed over six years. Hospital record databases were screened for the diagnosis of migraine with aura (MA) or without aura (MO), based on the ICHD-II criteria. Statistical analysis: Fisher's test or Mann-Whitney U test, significance at p < 0.05.
Results
Migraine was diagnosed in 495 children (29.7% MA, 70.3% MO). The majority of diagnoses were made between ages 9 and 14 years. After stratification for age into five groups, we observed an increase of diagnoses in females, with a peak after the age of 15 years, and an increase of MA. In both groups, the attacks were usually severe, infrequent (<1–3/month) lasting <2 hours, and associated with nausea/vomiting, photophobia, phonophobia (more frequent in MO). Osmophobia was reported in 24.7% of the patients with MO. Dizziness was more frequent in patients with MA. Visual auras were the most common occurrence (87.1%). Confusional state was observed in 10.88% of the patients. A positive family history of headache was observed in >88% of the patients.
Conclusion
We describe the characteristics of pediatric migraine based on the ICHD-II criteria, showing a likely significant loss of diagnoses using the ICHD-III beta. The incidence of migraine increases with age. MO occurs more commonly and shows more frequent attacks and a higher prevalence of associated symptoms, in particular osmophobia. Although males are prevalent in the entire sample, the proportion of females is higher among patients with MA in all of the age groups. Phenotype and sexual prevalence of migraine acquire adult characteristics and become more frequent in females from the onset of puberty.
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Ceylan, M., Bayraktutan, O. F., Becel, S., Atis, O., Yalcin, A., Kotan, D., 2015-09-30 06:50:45 AM
Background
Several studies have been conducted on the inflammatory aspects of migraine. Pentraxins are a novel and important part of innate immunity as a superfamily of acute phase proteins. In our study, we aimed to demonstrate the relationship between migraine and the serum levels of pentraxin-3 (PTX-3), C-reactive protein (CRP), fibrinogen and D-dimer.
Methods
We recruited 30 migraine patients (in both the attack and interictal period) and 30 healthy controls. Serum samples were obtained from all participants, and a brain MRI performed in the last six months was assessed regarding the presence of deep white matter lesions. Comparisons between the attack, interictal and control groups regarding the serum levels of PTX-3, CRP, fibrinogen and D-dimer were performed. The association between serum PTX-3 levels and migraine characteristics (disease duration, headache frequency, MRI findings, aura, family history, attack duration, and MIDAS score) was also assessed.
Results
We found higher serum levels of fibrinogen and PTX-3 in migraine attack patients compared with the interictal and control groups (p = 0.03 and p < 0.001, respectively). Subgroup analysis also showed that patients with a disease duration of more than five years and with an attack duration of more than 12 hours have lower serum levels of PTX-3 than patients who have a relatively new diagnosis and have relatively short-lasting migraine attacks (p = 0.042 and p = 0.038, respectively).
Conclusions
PTX-3 and fibrinogen exhibit different serum levels in patients undergoing a migraine attack compared with the interictal group and the controls. Participants with longer attacks and disease durations have lower serum levels of PTX-3, suggesting that inflammatory processes change along with disease progression.
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Bratbak, D. F., Nordgard, S., Stovner, L. J., Linde, M., Folvik, M., Bugten, V., Tronvik, E., 2015-09-30 06:50:45 AM
Objective
The main object of this pilot study was to investigate the safety of administering onabotulinumtoxinA (BTA) towards the sphenopalatine ganglion (SPG) in intractable chronic cluster headache. Efficacy data were also collected to provide indication on whether future placebo-controlled studies should be performed.
Method
In a prospective, open-label, uncontrolled study, we performed a single injection of 25 IU (n = 5) or 50 IU BTA (n= 5) towards the SPG in 10 patients with intractable chronic cluster headache with a follow-up of 24 weeks. The primary outcome was adverse events (AEs) and the main efficacy outcome was attack frequency in weeks 3 and 4 post-treatment.
Results
A total of 11 AEs were registered. There was one severe adverse event (SAE): posterior epistaxis. The number of cluster headache attacks (main efficacy outcome) was statistically significantly reduced in the intention-to-treat analysis from 18 ± 12 per week in baseline to 11 ± 14 (p = 0.038) in weeks 3 and 4, and five out of 10 patients had at least 50% reduction of attack frequency compared to baseline. The cluster attack frequency was significantly reduced for five out of six months post-treatment.
Conclusion
Randomised, placebo-controlled studies are warranted to establish the potential of this possible novel treatment of cluster headache.
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de Tommaso, M., Sciruicchio, V., Ricci, K., Montemurno, A., Gentile, F., Vecchio, E., Barbaro, M. G. F., Simeoni, M., Goffredo, M., Livrea, P., 2015-09-30 06:50:45 AM
Objectives
Few studies have addressed central sensitization symptoms and pain processing in childhood migraine. Our aims were to examine pain sensitivity and responses, including habituation, evoked by CO2 laser stimuli (laser-evoked potentials (LEPs)) in a cohort of children with migraine compared to non-migraine controls and to determine the correlation between LEP features and signs of central sensitization.
Methods
Thirty-five patients 8–15 years of age with migraines without aura were evaluated during the inter-critical phase and were compared to 17 controls. LEPs were analyzed, and their main features were correlated with clinical symptoms including allodynia and pericranial tenderness.
Results
The laser-evoked pain threshold was lower and the N2P2 vertex complex amplitude was higher in children with migraines. Furthermore, habituation of vertex waves of LEPs clearly showed a tendency toward progressive amplitude enhancement in the migraine group. Acute allodynia and inter-critical pericranial tenderness correlated with trigeminal LEP features, particularly with the abnormal habituation pattern.
Discussion
Abnormalities of pain processing and symptoms of central sensitization appear to be characteristics of children with migraine. Reduced habituation and progressive amplification of cortical responses to laser stimuli indicate an overactive nociceptive system at the onset of migraine, and this hyperactivity may subtend allodynia and pericranial tenderness. Future prospective trials may aid in the early identification of clinical phenotypes that display a tendency to develop into the chronic form of migraine, warranting a timely therapeutic approach.
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Luedtke, K., Allers, A., Schulte, L. H., May, A., 2015-09-30 06:50:45 AM
Aim
We aimed to conduct a systematic review evaluating the effectiveness of interventions used by physiotherapists on the intensity, frequency and duration of migraine, tension-type (TTH) and cervicogenic headache (CGH).
Methods
We performed a systematic search of electronic databases and a hand search for controlled trials. A risk of bias analysis was conducted using the Cochrane risk of bias tool (RoB). Meta-analyses present the combined mean effects; sensitivity analyses evaluate the influence of methodological quality.
Results
Of 77 eligible trials, 26 were included in the RoB assessment. Twenty trials were included in meta-analyses. Nineteen out of 26 trials had a high RoB in >1 domain. Meta-analyses of all trials indicated a reduction of TTH (p< 0.0001; mean reduction –1.11 on a 0–10 visual analog scale (VAS); 95% CI –1.64 to –0.57) and CGH (p = 0.0002; mean reduction –2.52 on a 0–10 VAS; 95% CI –3.86 to –1.19) pain intensity, CGH frequency (p < 0.00001; mean reduction –1.34 days per month; 95% CI –1.40 to –1.28), and migraine (p = 0.0001; mean reduction –22.39 hours without relief; 95% CI –33.90 to –10.88) and CGH (p < 0.00001; mean reduction –1.68 hours per day; 95% CI –2.09 to –1.26) duration. Excluding high RoB trials increased the effect sizes and reached additional statistical significance for migraine pain intensity (p < 0.00001; mean reduction –1.94 on a 0–10 VAS; 95% CI –2.61 to –1.27) and frequency (p < 0.00001; mean reduction –9.07 days per month; 95% CI –9.52 to –8.62).
Discussion
Results suggest a statistically significant reduction in the intensity, frequency and duration of migraine, TTH and CGH. Pain reduction and reduction in CGH frequency do not reach clinically relevant effect sizes. Small sample sizes, inadequate use of headache classification, and other methodological shortcomings reduce the confidence in these results. Methodologically sound, randomized controlled trials with adequate sample sizes are required to provide information on whether and which physiotherapy approach is effective. According to Grading of Recommendations Assessment, Development and Evaluation (GRADE), the current level of evidence is low.
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Cho, S.-J., Kim, B.-K., Kim, B.-S., Kim, J.-M., Kim, S.-K., Moon, H.-S., Song, T.-J., Cha, M.-J., Park, K.-Y., Sohn, J.-H., 2015-09-30 06:50:45 AM
Background
Vestibular migraine (VM), the common term for recurrent vestibular symptoms with migraine features, has been recognized in the appendix criteria of the third beta edition of the International Classification of Headache Disorders (ICHD-3β). We applied the criteria for VM in a prospective, multicenter headache registry study.
Methods
Nine neurologists enrolled consecutive patients visiting outpatient clinics for headache. The presenting headache disorder and additional VM diagnoses were classified according to the ICHD-3β. The rates of patients diagnosed with VM and probable VM using consensus criteria were assessed.
Results
A total of 1414 patients were enrolled. Of 631 migraineurs, 65 were classified with VM (10.3%) and 16 with probable VM (2.5%). Accompanying migraine subtypes in VM were migraine without aura (66.2%), chronic migraine (29.2%), and migraine with aura (4.6%). Probable migraine (75%) was common in those with probable VM. The most common vestibular symptom was head motion-induced dizziness with nausea in VM and spontaneous vertigo in probable VM. The clinical characteristics of VM did not differ from those of migraine without VM.
Conclusion
We diagnosed VM in 10.3% of first-visit migraineurs in neurology clinics using the ICHD-3β. Applying the diagnosis of probable VM can increase the identification of VM.
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Lane, R., Davies, P., 2015-09-30 06:50:45 AM
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Klein, J., Sandi-Gahun, S., Schackert, G., Juratli, T. A., 2015-09-30 06:50:45 AM
Objective
Peripheral nerve field stimulation (PNFS) is a promising modality for treatment of intractable facial pain. However, evidence is sparse. We are therefore presenting our experience with this technique in a small patient cohort.
Methods
Records of 10 patients (five men, five women) with intractable facial pain who underwent implantation of one or several subcutaneous electrodes for trigeminal nerve field stimulation were retrospectively analyzed. Patients' data, including pain location, etiology, duration, previous treatments, long-term effects and complications, were evaluated.
Results
Four patients suffered from recurrent classical trigeminal neuralgia, one had classical trigeminal neuralgia and was medically unfit for microvascular decompression. Two patients suffered from trigeminal neuropathy attributed to multiple sclerosis, one from post-herpetic neuropathy, one from trigeminal neuropathy following radiation therapy and one from persistent idiopathic facial pain. Average patient age was 74.2 years (range 57–87), and average symptom duration was 10.6 years (range 2–17). Eight patients proceeded to implantation after successful trial. Average follow-up after implantation was 11.3 months (range 5–28). Using the visual analog scale, average pain intensity was 9.3 (range 7–10) preoperatively and 0.75 (range 0–3) postoperatively. Six patients reported absence of pain with stimulation; two had only slight constant pain without attacks.
Conclusion
PNFS may be an effective treatment for refractory facial pain and yields high patient satisfaction.
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Schulte, L., May, A., 2015-09-30 06:50:45 AM
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Hagen, K., Wisloff, U., Ellingsen, O., Stovner, L. J., Linde, M., 2015-09-30 06:50:45 AM
Background
Evidence on the association between headache and physical fitness is conflicting. The aim of this population-based study was to examine the relationship between peak oxygen uptake (VO2peak) and headache, including migraine and tension-type headache (TTH).
Methods
In the third Nord-Trøndelag Health study (HUNT3), VO2peak was measured by ergospirometry in a sample of 4631 healthy adult participants. Of these, 3899 (54% women) also answered headache questions. The cross-sectional association between headache and VO2peak was evaluated by logistic regression using a categorical approach based on quintiles. Scores in the upper quintile were used as reference.
Results
Participants age 20–50 years had significant trends of increasing prevalence of any headache (p < 0.001), migraine (p < 0.001), TTH (p = 0.002) and unclassified headache (p = 0.027) with lower VO2peak. The highest prevalence odds ratios (ORs) were found in those with VO2peak in the lower quintile: For any headache the OR was 2.3 (95% confidence interval (1.6–3.3), for TTH 1.8 (1.2–2.8), for unclassified headache 1.9 (1.1–3.8), and for migraine 3.7 (2.1–6.6). Similar results were also found among those who reported physical activity levels in accordance with current recommendations of the American College of Sports Medicine but nevertheless had low VO2peak. Being in the lowest VO2peak quintile was also strongly associated with migraine aggravated by physical activity (OR 4.1, 2.1–8.1). No significant association was found between VO2peak and headache for those 50 years or older.
Conclusions
In this large cross-sectional study, an inverse relationship was found between VO2peak and headache for adults younger than 50 years of age.
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Chen, P.-K., Fuh, J.-L., Wang, S.-J., 2015-09-30 06:50:45 AM
Objective
Migraine is comorbid with restless legs syndrome (RLS). However, the temporal association between these two episodic disorders remains elusive. The current study investigated the temporal relationship between migraine and RLS attacks.
Methods
Migraine patients with RLS were recruited from a headache clinic. Patients with symptomatic RLS, RLS mimics, daily headaches, or daily RLS attacks were excluded. The patients recorded their headaches and RLS attacks for two weeks in a diary. The severity of each headache or RLS attack was rated on a four-point (0–3) Likert scale. Logit-normal, random-effects models were employed to estimate the odds ratios (ORs) for the temporal association between migraine and RLS attacks.
Results
Thirty migraine patients with RLS (28 F/2 M, mean age 35.5 ± 9.0 years) completed the study. On the basis of 420 daily diary records, migraine attacks were associated with subsequent RLS attacks occurring on the same and next nights (OR = 6.94, 95% confidence interval (CI) = 4.39–11.0 and OR = 3.00, CI = 1.92–4.68; both p < 0.001). RLS attacks were associated with subsequent migraine attacks only on Day 1 (OR = 1.97 (CI = 1.3–2.98;p = 0.01). Overall, the frequencies of migraine and RLS attacks in two weeks were correlated (Spearman's correlation = 0.56, p = 0.001).
Conclusions
Our study results showed a bidirectional triggering association between migraine and RLS attacks. The association was stronger and lasted longer for migraine triggering subsequent RLS than that for vice versa.
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Seo, J.-G., Park, S.-P., 2015-09-30 06:50:45 AM
Background
Almost one-third of patients with migraine do not adequately respond to triptans. We examined factors contributing to frovatriptan response in patients with migraine.
Methods
We enrolled new patients with migraine who consecutively visited our headache clinic. Eligible patients were instructed to take 2.5 mg of frovatriptan as soon as possible after migraine attack. The responsiveness was determined by whether headache was relieved or absent within 4 hours after the intake of frovatriptan. We assessed frovatriptan to be efficacious when headache responded to its administration in at least one of two successive migraine attacks and inefficacious when headache was not relieved in either attack. We included demographic, clinical and psychiatric variables in the analysis of factors associated with frovatriptan response.
Results
Of 128 eligible patients, 28 (21.9%) experienced frovatriptan inefficacy. In 24 patients with current major depressive disorder, 12 (50.0%) had frovatriptan inefficacy. Only current major depressive disorder was identified as a risk factor for inefficacy (odds ratio = 5.500, 95% confidence interval 2.103–14.382, p = 0.001).
Conclusions
Depression may be a risk factor of frovatriptan inefficacy in patients with migraine, even though half of patients with major depressive disorder respond to frovatriptan.
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Olesen, J., 2015-09-30 06:50:45 AM
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Viana, M., Linde, M., Sances, G., Ghiotto, N., Guaschino, E., Allena, M., Terrazzino, S., Nappi, G., Goadsby, P. J., Tassorelli, C., 2015-09-30 06:50:45 AM
Background
As there are no biological markers, a detailed description of symptoms, particularly temporal characteristics, is crucial when diagnosing migraine aura. Hitherto these temporal aspects have not been studied in detail.
Methods
We conducted a prospective diary-aided study of the duration and the succession of aura symptoms and their temporal relationship with headache.
Results
Fifty-four patients completed the study recording in a diary the characteristics of three consecutive auras (n = 162 auras). The median duration of visual, sensory and dysphasic symptoms were 30, 20 and 20 minutes, respectively. Visual symptoms lasted for more than one hour in 14% of auras (n = 158), sensory symptoms in 21% of auras (n = 52), and dysphasic symptoms in 17% of auras (n = 18). Twenty-six percent of patients had at least one aura out of three with one symptom lasting for more than one hour. In aura with multiple symptoms the subsequent symptom, second versus first one or third versus second, might either start simultaneously (34 and 18%), during (37 and 55%), with the end (5 and 9%), or after (24 and 18%) the previous aura symptom. The headache phase started before the aura (9%), simultaneously with the onset of aura (14%), during the aura (26%), simultaneously with the end of aura (15%) or after the end of aura (36%).
Conclusion
We provide data to suggest that symptoms may last longer than one hour in a relevant proportion of auras or migraine with aura patients, and that there is a high variability of scenarios in terms of time relationship among aura symptoms and between aura and headache.
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Minen, M. T., Loder, E., Tishler, L., Silbersweig, D., 2015-09-30 06:50:45 AM
Background
Studies reveal that migraine is often under-recognized, misdiagnosed and inadequately treated in the primary care setting.
Objective
The objective of this article is to assess primary care providers' (PCP) knowledge and needs regarding migraine diagnosis and management.
Methods
We held semi-structured group interviews and distributed a brief questionnaire to PCPs in our hospital network. Building on the information from the interviews, we developed a comprehensive survey assessing PCPs' knowledge about migraine. Descriptive analyses were performed.
Results
The initial interviews and brief questionnaires revealed that PCPs are aware of the prevalence of migraine but are uncertain about the details of management. Eighty-three of 120 physicians completed the comprehensive survey. Only 47% would order imaging for a new type of headache, 31% for worsening headache, and 35% for a headache unresponsive to treatment. Only 28% were familiar with the American Academy of Neurology guidelines on preventive treatment and 40% were familiar with the Choosing Wisely Campaign recommendations on migraine treatment. Just 34% were aware that opioids can cause medication-overuse headache. Non-pharmacologic treatment was not usually recommended. PCPs favored educational opportunities involving direct contact with headache physicians (56%).
Conclusions
PCPs are not universally aware of the specific recommendations for managing migraine patients. Future work should focus on innovative ways to provide decision support and education for PCPs caring for migraineurs.
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Chiang, C.-C., Schwedt, T. J., Wang, S.-J., Dodick, D. W., 2015-09-30 06:50:45 AM
Introduction
The objective of this review is to provide an evidence-based discussion of different treatment strategies for medication-overuse headache (MOH).
Method
We searched PubMed for articles discussing the treatment and prognosis of MOH published between 2004 and August 2014. Titles, abstract and articles were reviewed systematically. The level of evidence provided by each study of the included articles was determined according to the American Academy of Neurology Clinical practice guideline manual. We discuss the level of evidence to support the early discontinuation/withdrawal of overused medications, the level of evidence to support the use of preventive treatment, the short- and long-term prognosis, and the outcome according to the class of drug overused in patients diagnosed with MOH.
Results
The initial search resulted in 1313 articles; 68 articles met our inclusion criteria and were discussed. The level of evidence to support early discontinuation of overused medications alone is low due to the absence of controlled studies. Adding preventive medication to early discontinuation led to a better outcome than early discontinuation alone. For patients with chronic migraine (CM) and medication overuse (MO), there are large randomized control trials supporting the use of onabotulinumtoxinA and topiramate without early discontinuation of overuse; however, the evidence is limited since data were obtained from post hoc analysis.
Conclusion
Considering current available evidence and the systemic toxicity of overusing acute headache medication, we suggest discontinuation of the overused medication with the addition of preventive medication. Appropriately sized, randomized controlled trials evaluating the safety and long-term efficacy of preventive medication plus early discontinuation of overuse vs preventive medication alone vs early discontinuation of overuse alone are needed.
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Asberg, A. N., Stovner, L. J., Zwart, J.-A., Winsvold, B. S., Heuch, I., Hagen, K., 2015-09-30 06:50:45 AM
Background
There is conflicting evidence for the association between migraine and increased mortality risk. The aim of this study was to investigate the relationship between migraine and non-migrainous headache, and all-cause mortality and cardiovascular mortality.
Methods
In this prospective population-based cohort study from Norway, we used baseline data from the second Nord-Trøndelag Health Survey (HUNT2), performed between 1995 and 1997 in the County of Nord-Trøndelag. These data were linked with a comprehensive mortality database with follow-up through the year 2011. A total of 51,853 (56% of invited) people were categorized based on their answers to the headache questions in HUNT2 (headache free, migraine or non-migrainous headache). Hazard ratios (HRs) of mortality during a mean of 14.1 years of follow-up were estimated using Cox regression.
Results
During the follow-up period 9408 died, 4321 of these from cardiovascular causes. There was no difference in all-cause mortality between individuals with migraine and non-migrainous headache compared to those without headache or between headache status and mortality by cardiovascular disease. There was, however, among men with migraine without aura a reduced risk of death by cardiovascular diseases (HR 0.72, 95% confidence interval 0.56–0.93). This relationship was not evident in women.
Conclusion
In this large, prospective cohort study there was no evidence for a higher all-cause mortality or cardiovascular mortality among individuals with migraine.
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Riesco, N., Perez-Alvarez, A. I., Verano, L., Garcia-Cabo, C., Martinez-Ramos, J., Sanchez-Lozano, P., Cernuda-Morollon, E., Pascual, J., 2015-09-30 06:50:45 AM
Background
Cranial autonomic symptoms (CAS) seem to appear in around half of migraine patients.
Objective
Our aim was to analyse the prevalence and profile of CAS, mainly of cranial autonomic parasympathetic symptoms (CAPS), in a series of patients with chronic migraine (CM) according the new criteria for autonomic symptoms in the current IHS classification.
Patients and methods
We recruited consecutive CM patients attending our headache clinic. Five CPAS were surveyed: lacrimation, conjunctival injection, eyelid oedema, ear fullness and nasal congestion. They were graded as 0 (absent), 1 (present and mild) and 2 (present and conspicuous); therefore the score in this CAPS scale ranges from 0 to 10 points. As a cranial autonomic sympathetic symptom (CSAS), we also asked about the presence of ptosis.
Results
We interviewed 100 CM patients. Their mean age was 45 years (18–63 years); 93 were females. Eighteen had no CAPS, while 82 reported at least one CAPS. There were only six patients with scores higher than 5, the mean and median CAPS being 2.1 and 2, respectively. Prevalence of CAPS was lacrimation (49%), conjunctival injection (44%), eyelid oedema (39%), ear fullness (30%) and nasal congestion (20%). Ptosis was reported by 42.
Conclusion
These results, by using for the first time an easy quantitative scale, confirm that (mild) CAPS are not the exception but the rule in CM patients. The score in this CAPS scale could be of help as a further endpoint in clinical trials or to be correlated with potential biomarkers of parasympathetic activation in primary headaches.
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Krogh, A.-B., Larsson, B., Salvesen, O., Linde, M., 2015-09-30 06:50:45 AM
Aim
The aim of this article was to develop and apply an Internet-based headache diary (i-diary) for adolescents and compare it with a paper-diary (p-diary) regarding adherence, user acceptability and recorded headache activity.
Methods
In a cross-sectional school-based study, a representative sample of 488 adolescents aged 12–18 years were randomly allocated by cluster sampling to record for three weeks in i-diaries or p-diaries their headache intensity, disability, and use of acute medication.
Results
A significantly (p = 0.008) higher proportion of adolescents in the i-diary group used the diary at least once during the 21-day period (86% vs 76% for the p-diary). However, the p-diary group completed a significantly (p< 0.001) higher number of diary days (20.8 vs 15.0 days for the i-diary). The response rate for the i-diary-group was largely evenly distributed over the study period; conversely, approximately two-thirds of the adolescents using the p-diary responded on all 21 days, whereas one-fourth did not respond at all. The two diary types were rated as equal in easiness to remember (p = 0.25), but the i-diaries were more bothersome to use (p = 0.029).
Conclusion
Although p-diary users completed a higher proportion of diary days, i-diaries provided more reliable and credible estimates of headache parameters because of better real-time assessment.
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John, S., Singhal, A. B., Calabrese, L., Uchino, K., Hammad, T., Tepper, S., Stillman, M., Mills, B., Thankachan, T., Hajj-Ali, R. A., 2015-09-30 06:50:45 AM
Background
Long-term outcomes of reversible cerebral vasoconstriction syndrome (RCVS) have not been systematically investigated.
Methods
The following validated questionnaires were mailed to patients recruited from the RCVS registries of two academic hospitals: headache screening form, Headache Impact Test, Migraine Disability Assessment Test, Barthel Index (BI), EuroQoL (EQ-5D-5L) and Patient Health Questionnaire (PHQ-9).
Results
Of the 191 patients in the registries, 109 could be contacted and 45 responded. Median follow-up time after symptom onset was 78 months. After RCVS resolution, 24 (53%) patients continued to have headache, but the majority (88%) reported improvement in its severity. Thirteen of the 24 patients with persistent headache had a history of migraine prior to RCVS diagnosis. The majority (97.5%) of respondents were functionally independent based on BI scores. EQ-5D-5L showed better scores in the domains of mobility, self-care and usual activities, as compared to pain and anxiety/depression. Patients with persistent headache had significantly higher levels of EQ-5D-5L pain scores. PHQ-9 scores revealed only one patient (3%) with severe depression.
Conclusion
More than half of RCVS patients will continue to have chronic headaches of mild to moderate intensity that are distinct from the "thunderclap" headaches at RCVS onset. The vast majority regain complete functional ability. However, pain and anxiety/depression are frequent, often aggravated by concomitant chronic headaches, and may be associated with lower quality of life.
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Sabre, L., Rugo, M., Asser, T., Korv, J., Braschinsky, M., 2015-09-30 06:50:45 AM
Background
Patients with traumatic spinal cord injury (TSCI) often suffer from different types of pain. However, headaches after TSCI have not been studied.
Aim
The aim of this article is to examine the occurrence of headache among patients with TSCI.
Methods
This cross-sectional study included individuals with TSCI from 1997 to 2012 in Estonia. Patients with TSCI were interviewed via telephone. The interview was based on a questionnaire specifically designed to identify headache type using the International Classification of Headache Disorders, third edition (beta version).
Results
There were 73 patients with a mean age 37.1 ± 10.6 years. The mean time since TSCI was 7.5 ± 4.0 years. The most frequently mentioned pain was headache (71%), followed by back pain (60%) and pain in neck (44%).
Headaches were more frequent after the trauma compared with the headaches before TSCI (71% vs 51%, p = 0.02). Headaches that arose after TSCI were not related to the concomitant brain injury (p = 0.15). The occurrence of headache did not depend on the severity or the level of the TSCI.
Eighty-five percent of patients had not contacted any physician and headache was not diagnosed.
Conclusions
This is the first study that evidentially shows that headache is the most prevalent pain condition after TSCI. Despite this, the majority of patients never consult a physician, nor is their headache diagnosed or appropriately managed. This indicates that further studies are needed to provide evidence regarding the prevalence and causes of headache and its impact on quality of life.
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Orr, S. L., 2015-09-30 06:50:45 AM
Background
The use of complementary and alternative medicines (CAM) is common among patients with primary headaches. In parallel, CAM research is growing. Diet interventions comprise another category of non-pharmacologic treatment for primary headache that is of increasing clinical and research interest.
Methods
A literature search was carried out to identify studies on the efficacy of diet and nutraceutical interviews for primary headache in the pediatric and adult populations. MEDLINE, Embase and EBM Reviews—Cochrane Central Register of Controlled Trials were searched to identify studies.
Results
There is a growing body of literature on the potential use of CAM and diet interventions for primary headache disorders. This review identified literature on the use of a variety of diet and nutraceutical interventions for headache. Most of the studies assessed the efficacy of these interventions for migraine, though some explored their role in tension-type headache and cluster headache. The quality of the evidence in this area is generally poor.
Conclusions
CAM is becoming more commonplace in the headache world. Several interventions show promise, but caution needs to be exercised in using these agents given limited safety and efficacy data. In addition, interest in exploring diet interventions in the treatment of primary headaches is emerging. Further research into the efficacy of nutraceutical and diet interventions is warranted.
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Pressman, A., Jacobson, A., Eguilos, R., Gelfand, A., Huynh, C., Hamilton, L., Avins, A., Bakshi, N., Merikangas, K., 2015-09-30 06:50:45 AM
Introduction
The growing availability of electronic health data provides an opportunity to ascertain diagnosis-specific cases via systematic methods for sample recruitment for clinical research and health services evaluation. We developed and implemented a migraine probability algorithm (MPA) to identify migraine from electronic health records (EHR) in an integrated health plan.
Methods
We identified all migraine outpatient diagnoses and all migraine-specific prescriptions for a five-year period (April 2008–March 2013) from the Kaiser Permanente, Northern California (KPNC) EHR. We developed and evaluated the MPA in two independent samples, and derived prevalence estimates of medically-ascertained migraine in KPNC by age, sex, and race.
Results
The period prevalence of medically-ascertained migraine among KPNC adults during April 2008–March 2013 was 10.3% (women: 15.5%, men: 4.5%). Estimates peaked with age in women but remained flat for men. Prevalence among Asians was half that of whites.
Conclusions
We demonstrate the feasibility of an EHR-based algorithm to identify cases of diagnosed migraine and determine that prevalence patterns by our methods yield results comparable to aggregate estimates of treated migraine based on direct interviews in population-based samples. This inexpensive, easily applied EHR-based algorithm provides a new opportunity for monitoring changes in migraine prevalence and identifying potential participants for research studies.
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Foote, H. W., Hamer, J. D., Roland, M. M., Landy, S. R., Smitherman, T. A., 2015-09-30 06:50:45 AM
Background
Studies of musculoskeletal pain patients confirm that acceptance of pain and values-based action are strong predictors of pain-related disability and that interventions fostering "psychological flexibility" confer positive outcomes. However, data on these processes in migraine remain limited. This cross-sectional study examined relations between components of psychological flexibility and headache among treatment-seeking migraineurs.
Methods
A total of 103 adults (M age = 41.5 (11.9) years; 88.2% female) with ICHD-confirmed migraine (71.8% episodic, 28.2% chronic) across three clinics completed measures of psychological flexibility and headache-related disability. Hierarchical regressions quantified relations between acceptance/values-based action and headache variables after first controlling for pain severity and gender.
Results
Acceptance of pain and values-based action accounted for 10% of unique variance in headache severity (R2 p = 0.006) and up to 20% in headache-related disability (R2 ps = 0.02 and < 0.001) but were weakly related to headache frequency. Psychological flexibility was more strongly associated with MIDAS-measured disability than was headache severity or headache frequency. Significant effects were typically of medium-to-large size and driven primarily by values-based action.
Conclusions
Paralleling results from the broader chronic pain literature, pain acceptance and values-based action play significant roles in headache pain and disability. Further study of interventions targeting these processes may enhance existing treatments.
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Ambrosini, A., Iezzi, E., Perrotta, A., Kisialiou, A., Nardella, A., Berardelli, A., Pierelli, F., Schoenen, J., 2015-09-30 06:50:45 AM
Introduction
In migraine most studies report an interictal deficit of habituation of visual-evoked potentials (VEP-hab) and reduced thresholds for phosphene induction (PT) by transcranial magnetic stimulation (TMS). We searched for a possible correlation between VEP-hab and PT in migraine patients and healthy controls to test whether they reflect the same pathophysiological abnormality.
Methods
We assessed PT and VEP-hab measured as the percentage change of N1/P1 amplitude over six blocks of 100 responses in 15 healthy volunteers (HV) and in 13 episodic migraineurs without aura (MO) between attacks. Results were compared using Mann-Whitney U test. Interrelationships were examined using Spearman's correlation.
Results
In MO patients VEP-hab was reduced compared to HV (p = 0.001), while PT were not significantly different between HV and MO. There was no correlation between PT and VEP-hab in either group of participants.
Conclusions
We confirm that in interictal migraine VEP habituation is deficient, but magnetophosphene threshold normal. VEP-hab and PT were not correlated with each other in healthy controls or in migraineurs. This finding suggests that they index different facets of cortical excitability in migraine, i.e. a punctual normal measure of the cortical activation threshold for PT and a dynamic response pattern to repeated stimuli for VEP habituation.
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Heyer, G. L., Young, J. A., Rose, S. C., McNally, K. A., Fischer, A. N., 2015-09-30 06:50:45 AM
Objective
The term "post-traumatic migraine" (PTM) has been used to describe post-traumatic headaches (PTHs) that have associated migraine features, but studies of this relationship are lacking. The objective of the present study was to determine whether PTH correlates strongly with migraine symptoms among youth with concussion.
Methods
Twenty-three symptoms were analyzed from a retrospective cohort of 1953 pediatric patients with concussion. A principal component analysis (PCA) with oblique Promax rotation was conducted to explore underlying symptom relationships in the full cohort and in subcohorts stratified by the presence (n = 414) or absence (n = 1526) of premorbid headache.
Results
The mean patient age was 14.1 years; 63% were male. Headache was the most common postconcussion symptom, acknowledged by 69.4% of patients. When considering the full cohort, the PCA demonstrated clustering of headache with photophobia, phonophobia, nausea, dizziness, and neck pain. Similar clustering was present among patients without premorbid headaches. Repeating the analysis in the patients with preconcussion headaches led to elimination of neck pain from the cluster.
Conclusions
PTH correlates strongly with other migraine symptoms among youth with concussion, regardless of premorbid headaches. This clustering of migraine symptoms supports the existence of PTM as a distinct clinical entity in some patients.
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Husoy, A. K., Indergaard, M. K., Honningsvag, L.-M., Haberg, A. K., Hagen, K., Linde, M., Garseth, M., Stovner, L. J., 2015-09-30 06:50:45 AM
Background
In four previous clinic-based MRI studies headache sufferers (in particular migraineurs) had more perivascular spaces (PVS) than individuals who were headache-free.
Methods
The present study was part of a large longitudinal, epidemiological study (Nord-Trøndelag Health Survey (HUNT)). The 1006 participants, age 50–65 years at inclusion, had participated in all previous HUNT surveys (1–3), and been randomly selected to a population-based imaging study of the head (HUNT-MRI, 2007–2009). The number of visible PVS in the basal ganglia (BG) and hemispheric white matter (HWM) was compared in headache sufferers (migraine with and without aura, non-migrainous headache) and people who were headache-free.
Results
The results showed in general small differences between headache sufferers and headache-free participants. In the cross-sectional analysis migraineurs without aura had fewer PVS than headache-free individuals in BG (OR = 0.84, 95% CI = 0.76--0.94, p value = 0.003) and in BG and HWM together (OR = 0.97, 95% CI = 0.95-1.00, pvalue = 0.046). No difference between long-term headache sufferers and long-term headache-free individuals with regard to number of PVS was found.
Discussion
In contrast to previous studies, the present large, blinded, population-based study showed no increase in number of dilated PVS among headache sufferers. Fewer PVS among those with migraine without aura may be a spurious finding.
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Kobayashi, M., 2015-09-30 06:50:45 AM
Background
Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by recurrent thunderclap headaches with reversible cerebral vasoconstriction, and often precipitated by the postpartum state and vasoactive medications. We describe a case of a patient with RCVS induced by amezinium metilsulfate, a sympathomimetic drug, in whom magnetic resonance angiography (MRA) initially revealed diffusely dilated cerebral arteries.
Case description
A 34-year-old woman was prescribed amezinium metilsulfate for hypotension. Twelve days later, she suffered from abrupt severe headaches and was referred to our department. She had no neurological deficits; however, MRA revealed diffusely dilated anterior, middle, and posterior cerebral arteries with vasoconstriction. She was tentatively diagnosed with RCVS and successfully treated with verapamil for headache. Nevertheless, follow-up MRAs disclosed widespread segmental vasoconstriction that resolved in two months.
Discussion
Diffuse cerebrovascular dilation has not been addressed but may be associated with RCVS pathophysiology. In addition, physicians should bear in mind that amezinium metilsulfate can potentially induce RCVS.
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Bilgic, B., Kocaman, G., Arslan, A. B., Noyan, H., Sherifov, R., Alkan, A., Asil, T., Parman, Y., Baykan, B., 2015-09-30 06:50:45 AM
Background
Chronic migraine (CM) is a disabling neurologic condition that often evolves from episodic migraine. There has been mounting evidence on the volumetric changes detected by magnetic resonance imaging (MRI) technique in migraineurs. These studies mainly focused on episodic migraine patients and less is known about the differences in CM patients.
Method
A total of 24 CM patients and 24 healthy control individuals (all females) were included in this study. All participants underwent neurological examination and MRI. High-resolution anatomical MRI images were processed with an automated segmentation method (FreeSurfer). White-matter abnormalities of the brain were also evaluated with the Age-Related White-Matter-Changes Scale.
Results
The volumes of the cerebellum and brainstem were found to be smaller in CM patients compared to healthy controls. White-matter abnormalities were also found in CM patients, specifically in the bilateral parieto-occipital areas. There was no correlation between the clinical variables and volume decrease in these regions.
Conclusion
CM patients showed significant volume differences in infratentorial areas and white-matter abnormalities in the posterior part of the brain. It is currently unclear whether the structural brain changes seen in migraine patients are the cause or the result of headaches. Longitudinal volumetric neuroimaging studies with larger groups, especially on the chronification of migraine, are needed to shed light on this topic.
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Lipton, R. B., Serrano, D., Buse, D. C., Pavlovic, J. M., Blumenfeld, A. M., Dodick, D. W., Aurora, S. K., Becker, W. J., Diener, H.-C., Wang, S.-J., Vincent, M. B., Hindiyeh, N. A., Starling, A. J., Gillard, P. J., Varon, S. F., Reed, M. L., 2015-09-30 06:50:45 AM
Background
Migraine, particularly chronic migraine (CM), is underdiagnosed and undertreated worldwide. Our objective was to develop and validate a self-administered tool (ID-CM) to identify migraine and CM.
Methods
ID-CM was developed in four stages. (1) Expert clinicians suggested candidate items from existing instruments and experience (Delphi Panel method). (2) Candidate items were reviewed by people with CM during cognitive debriefing interviews. (3) Items were administered to a Web panel of people with severe headache to assess psychometric properties and refine ID-CM. (4) Classification accuracy was assessed using an ICHD-3β gold-standard clinician diagnosis.
Results
Stages 1 and 2 identified 20 items selected for psychometric validation in stage 3 (n = 1562). The 12 psychometrically robust items from stage 3 underwent validity testing in stage 4. A scoring algorithm applied to four symptom items (moderate/severe pain intensity, photophobia, phonophobia, nausea) accurately classified most migraine cases among 111 people (sensitivity = 83.5%, specificity = 88.5%). Augmenting this algorithm with eight items assessing headache frequency, disability, medication use, and planning disruption correctly classified most CM cases (sensitivity = 80.6%, specificity = 88.6%).
Discussion
ID-CM is a simple yet accurate tool that correctly classifies most individuals with migraine and CM. Further testing in other settings will also be valuable.
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Steppacher, I., Schindler, S., Kissler, J., 2015-09-30 06:50:45 AM
Background
Migraine is a disorder of periodic disabling headache. Facilitated cortical responsivity has been suggested as one predisposing factor. Although the underlying mechanisms of migraine attack onsets are not fully understood, facilitated cortical responsivity has been suggested as one predisposing factor. Here, we investigate if enhanced cortical responsivity is reflected in altered event-related potentials during processing of complex pictures.
Method
Altogether, 16 migraine patients and 16 healthy volunteers participated in this study. Each patient had a diagnosed migraine and was headache- and medication-free for the study. Participants watched positive, negative and neutral pictures from the international affective picture system. An electroencephalogram was recorded during picture presentation. Afterwards, participants were asked to rate the pictures for valence and arousal.
Results
Migraine patients showed significantly more negative-going early event-related potential components from 100 ms to 180 ms to all picture categories over occipital regions as well as more positive-going late potentials over central regions. Patients and controls did not differ in valence and arousal ratings for the international-affective picture system.
Discussion
Patients with migraine seem to react cortically more intensely to all kinds of pictorial stimuli, regardless of emotional content. This facilitated processing may be related to the high cortical responsivity shown in various other event-related potential studies and might contribute to the recurring intense headache attacks.
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Garcia-Moreno, H., Cuadrado, M.-L., 2015-09-30 06:50:45 AM
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Zhang, Y., Kong, Q., Chen, J., Li, L., Wang, D., Zhou, J., 2015-09-30 06:50:45 AM
Objectives
This study explored the clinical characteristics of vestibular migraine in Chinese subjects and performed a field test of the criteria of the International Classification of Headache Disorders 3rd edition beta version.
Methods
Consecutive patients with vestibular migraine were surveyed and registered in a headache clinic during the study period. The diagnosis of vestibular migraine was made according to International Classification of Headache Disorders 3rd edition beta version. Assessments included standardized neuro-otology bedside examination, pure-tone audiogram, bithermal caloric testing, neurological imaging, cervical X-ray or magnetic resonance imaging, Doppler ultrasound of cerebral arteries and laboratory tests.
Results
A total of 67 patients (62 female/five male, 47.8 ± 10.3 years old) were enrolled in this study. The mean ages of migraine and vertigo onset were 32.2 ± 11.5 and 37.9 ± 10.1 years, respectively. The most common migraine subtype was migraine without aura (79%), followed by migraine with aura (12%) and chronic migraine (9%). The duration of vertigo attacks varied from seconds to days and 25% of patients had attacks that lasted less than 5 minutes. Among the patients with short-lasting attacks, 75% of these patients had ≥5 attacks per day within 72 hours. Auditory symptoms were reported in 36% of the patients. Migraine prophylactic treatments were effective in 77% of the patients.
Conclusions
Our study showed that the clinical features of vestibular migraine in China were similar to those of Western studies. The definition of vertigo episodes and migraine subtypes of vestibular migraine in International Classification of Headache Disorders 3rd edition beta version might be modified further. More than five vertigo attacks per day within 72 hours might be helpful as far as identifying vestibular migraine patients with short-lasting attacks.
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Koenig, J., Williams, D. P., Kemp, A. H., Thayer, J. F., 2015-09-30 06:50:45 AM
Objective
Vagal nerve activity—indexed by heart rate variability (HRV)—has been linked to altered pain processing and inflammation, both of which may underpin headache disorders and lead to cardiovascular disease (CVD). Here we examined the evidence for differences in parasympathetic (vagal) activity indexed by time- and frequency-domain measures of HRV in patients with headache disorders compared to healthy controls (HCs).
Methods
A systematic review and meta-analysis was conducted on studies investigating group differences in vagally mediated HRV (vmHRV) including time- (root-mean-square of successive R-R-interval differences (RMSSD)) and frequency- (high-frequency HRV) domain measures. Studies eligible for inclusion were identified by a systematic search of the literature, based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.
Results
Seven studies reporting a total of 10 comparisons of patients with headache disorders (HF-HRV n = 67, RMSSD n= 122) and HCs (HF-HRV n = 64, RMSSD n = 125) were eligible for inclusion. Random-effects meta-analysis revealed a significant main effect on RMSSD (Z = 2.03, p = 0.04; Hedges' g = –0.63; 95% CI (–1.24, –0.02); k = 6) and similar pooled effect size estimates for HF-HRV when breathing was controlled (g = –0.30; 95% CI (–0.69; 0.10)) but not when breathing was not controlled (g = 0.02; 95% CI (–0.69; 0.74)). Controlling for breathing had no effect on RMSSD.
Conclusion
vmHRV is reduced in patients with headache disorders, findings associated with a medium effect size. Suggestions for future research in this area are provided, emphasizing a need to investigate the impact of headache disorders and commonly comorbid conditions—including mental disorders—as well as the investigation of the risk for CVD in migraine in particular. We further emphasize the need for large-scale studies to investigate HRV as a mechanism mediating the association of migraine and CVD.
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Postma, I., van Oosterhout, W., de Groot, J., Terwindt, G., Zeeman, G., 2015-09-30 06:50:45 AM
Introduction
Identifying female-specific risk markers for cerebrovascular disease is becoming increasingly important. Both migraine and preeclampsia have been associated with higher incidence of brain white matter lesions (WML) and stroke. We assessed the association between WML and migraine among formerly (pre)eclamptic women.
Methods
A total of 118 women (76 formerly (pre)eclamptic and 42 control women) were screened for migraine and WML presence. Independent effects of migraine and (pre)eclampsia on WML were assessed.
Results
Migraine prevalence did not differ between the (pre)eclamptic (26/76; 34%); and control group (10/42; 24%), p= 0.17. Age-adjusted regression analysis failed to show a significant independent effect of migraine (OR 1.14; 95% CI 0.47–2.76; p = 0.77) on WML presence, and showed a non-significant effect of (pre)eclampsia (OR 2.30; 95% CI 0.90–5.83; p = 0.08).
Conclusion
Migraine prevalence was not found to be an independent risk factor for WML prevalence in formerly (pre)eclamptic women. Since this study had a small sample size, larger prospective studies are needed to examine female-specific risk factors for WML and its consequences.
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Gungor, F., Akyol, K. C., Kesapli, M., Celik, A., Karaca, A., Bozdemir, M. N., Eken, C., 2015-09-30 06:50:45 AM
Objective
Migraine is a leading headache etiology that frequently presents to the emergency department (ED). In the present study, we aimed to determine the efficacy of dexketoprofen in aborting migraine headaches in the ED.
Methods
This prospective, randomized, double-blind study was conducted in an ED of a tertiary care hospital using allocation concealment. Patients were allocated into two arms to receive the study drug; 50 mg dexketoprofen in 50 ml saline and 50 ml saline as placebo. Change in pain intensity was measured by the visual analog scale at baseline, both at 30 and 45 minutes after the study medication was administered. Rescue medication requirement and pain relapse were also recorded by a telephone follow-up at 48 hours.
Results
A total of 224 patients (112 in each group) were included into the final analysis. Mean age of the study participants was 37 ± 11 (SD) and 25% (n = 56) of them were male. The median pain improvement at 45 minutes for patients receiving dexketoprofen was 55 (IQR: 49 to 60) and 30 (IQR: 25 to 35) for those receiving placebo. The mean difference between the two groups at 45 minutes was 21.4 (95% CI: 14.4. to 28.5). Rescue drugs were needed in 22.3% of patients who received dexketoprofen compared to 55.4% in patients who received placebo (dif: 33.1%; 95% CI: 20% to 45%). There were no adverse events reported in either group during the study period.
Conclusion
Intravenous dexketoprofen is superior to placebo in relieving migraine headaches in the ED. It may be a suitable therapy with minimum side effects in patients presenting with a migraine headache to the ED.
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Blicher, J. U., Tietze, A., Donahue, M. J., Smith, S. A., Ostergaard, L., 2015-09-30 06:50:45 AM
Introduction
To investigate tissue flow disturbance and hypoxia during migraine aura, we studied a case of familial hemiplegic migraine (FHM) using novel magnetic resonance imaging (MRI) techniques.
Case results
A 44-year-old male was admitted with suspected stroke because of confusion and aphasia. Initial gadolinium-based perfusion MRI showed a decrease in cerebral blood flow and an increase in capillary flow disturbances within the left hemisphere. Later during the prolonged aura phase, chemical exchange saturation transfer MRI indicated a drop in pH in the affected area. The patient was diagnosed with an R908Q mutation in the ATP1A2gene causing FHM type 2.
Discussion
During prolonged aura in FHM, MRI shows reduced CBF, capillary flow disturbances and a possible pH drop that could indicate tissue hypoxia.
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Yamada, K., 2015-09-30 06:50:45 AM
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Chen, Y.-C., Wang, Y.-F., Li, J.-Y., Chen, S.-P., Lirng, J.-F., Hseu, S.-S., Tung, H., Chen, P.-L., Wang, S.-J., Fuh, J.-L., 2015-09-30 06:50:45 AM
Objective
The objective of this article is to elucidate the outcome, prognostic predictors and timing of surgical intervention for subdural hematoma (SDH) in patients with spontaneous intracranial hypotension (SIH).
Methods
Patients with SDH were identified retrospectively from 227 consecutive SIH patients. Data were collected on demographics, clinical courses, neuroimaging findings, and treatment of SDH, which was later divided into conservative treatment, epidural blood patches (EBP), and surgical intervention. Poor outcome was defined as severe neurological sequelae or death.
Results
Forty-five patients (20%) with SDH (mean maximal thickness 11.9 ± 6.2 mm) were recruited. All 15 patients with SDH <10 mm achieved good outcomes by either conservative treatment or EBP. Of 30 patients with SDH ≥10 mm, patients with uncal herniation (n = 3) had poor outcomes, even after emergent surgical evacuation (n = 2), compared to those without (n = 27) (100% vs. 0%, p < 0.001). Fourteen patients underwent surgical evacuation, resulting in good outcomes in all 12 who received early intervention and poor outcomes in the remaining two who received delayed intervention after Glasgow Coma Scale (GCS) score ≤8 (100% vs. 0%, p = 0.01).
Conclusions
Uncal herniation results in poor outcomes in patients with SIH complicated with SDH. In individuals with SDH ≥10 mm and decreased GCS scores, early surgical evacuation might prevent uncal herniation.
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Hansen, J. M., Goadsby, P. J., Charles, A. C., 2015-09-30 06:50:45 AM
Background
There is significant variability in the clinical presentation of migraine, both among patients, and between attacks in an individual patient. We examined clinical features of migraine with aura in a large group of patients enrolled in a clinical trial, and compared retrospective migraine attack characteristics reported upon enrollment in the trial with those recorded prospectively in the trial.
Methods
Patients with migraine (n = 267) with typical visual aura in more than 30% of their attacks were enrolled from 16 centers for a clinical trial. Upon enrollment, patients provided a detailed retrospective description of the clinical features of their attacks of migraine. During the trial, clinical symptoms in migraine attacks starting with aura were recorded prospectively in 861 attacks.
Results
Retrospectively reported visual aura symptoms were variable and often overlapping; the most common symptoms were dots or flashing lights, wavy or jagged lines, blind spots, and tunnel vision. Multiple patients reported more than one visual phenomenon. Approximately half of the patients reported nonvisual aura symptoms, the most common were numbness and tingling, followed by difficulty in recalling or speaking words. A significant percentage of patients also reported a change in olfaction. There were several inconsistencies between the features of prospectively recorded and retrospectively reported attacks. Headache, nausea, photophobia, and phonophobia were all less common in prospectively recorded attacks as compared with retrospective reporting. Nausea was prospectively recorded in only 51% of attacks and mostly with mild intensity. The occurrence and severity of nausea was reduced with advancing patient age. Phonophobia was not consistently recorded in conjunction with photophobia.
Conclusion
These findings are consistent with variable involvement of different brain regions during a migraine attack. The variable occurrence of nausea, and phonophobia in conjunction with photophobia, both defining features of migraine, may be an important consideration in designing clinical studies of migraine in which prospectively recorded attacks are diagnosed based on these clinical features.
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Burgos-Vega, C. C., Ahn, D. D.-U., Bischoff, C., Wang, W., Horne, D., Wang, J., Gavva, N., Dussor, G., 2015-09-30 06:50:45 AM
Background
Migraine headache is a neurological disorder affecting millions worldwide. However, little is known about the mechanisms contributing to migraine. Recent genome-wide association studies have found single nucleotide polymorphisms in the gene encoding transient receptor potential channel M8. Transient receptor potential channel M8 is generally known as a cold receptor but it has been implicated in pain signaling and may play a role in migraine pain.
Methods
In order to investigate whether transient receptor potential channel M8 may contribute to the pain of migraine, the transient receptor potential channel M8 activator icilin was applied to the dura mater using a rat behavioral model of headache. Cutaneous allodynia was measured for 5 hours using Von Frey filaments.
Results
: Dural application of icilin produced cutaneous facial and hind paw allodynia that was attenuated by systemic pretreatment with the transient receptor potential channel M8-selective antagonist AMG1161 (10 mg/kg p.o.). Further, the anti-migraine agent sumatriptan (0.6 mg/kg s.c.) or the non-selective NOS inhibitor L-NAME (20 mg/kg i.p.) also attenuated allodynia when given as a pretreatment.
Conclusions
These data indicate that transient receptor potential channel M8 activation in the meninges produces behaviors in rats that are consistent with migraine and that are sensitive to pharmacological mechanisms known to have efficacy for migraine in humans. The findings suggest that activation of meningeal transient receptor potential channel M8 may contribute to the pain of migraine.
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Bourvis, N., Franc, J., Szatmary, Z., Chabriat, H., Crassard, I., Ducros, A., 2015-09-30 06:50:45 AM
Introduction
Reversible cerebral constriction syndrome and cerebral venous thrombosis are two rare conditions. Reversible cerebral constriction syndrome affects the cerebral arteries and the pathology is still largely unknown. To date, no physiological link with cerebral venous thrombosis has been reported.
Case results
We report here the case of a 24-year-old woman who presented a reversible cerebral constriction syndrome in the setting of a cerebral venous thrombosis. Cerebral venous thrombosis had developed in her left lateral venous sinus, within the stent placed one year before, in order to treat an idiopathic intracranial hypertension.
Discussion
The co-occurrence of cerebral venous thrombosis and reversible cerebral constriction syndrome in the same patient raises the issue of a potential link between them. We discuss the potential common trigger factors in this case: recent hormonal therapy; intracranial hypotension iatrogenically induced by lumbar puncture.
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Gottschalk, P. C. H., 2015-09-30 06:50:45 AM
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Amemiya, S., Takahashi, K., Mima, T., Yoshioka, N., Miki, S., Ohtomo, K., 2015-09-30 06:50:45 AM
Aim
The aim of this article is to investigate the pathophysiology underlying the alternation of the cognitive function and neuronal activity in spontaneous intracranial hypotension (SIH).
Methods
Fifteen patients with SIH underwent resting-state functional magnetic resonance imaging and working-memory (WM) test one day before and one month after a surgical operation. Alternation of the cognitive function and spontaneous neuronal activity measured as amplitude of the low-frequency fluctuations (ALFF) and the functional connectivity of the default-mode network (DMN) and frontoparietal networks (FPNs) were evaluated.
Results
WM performance significantly improved post-operatively. Whole-brain linear regression analysis of the ALFF revealed a positive correlation between cognitive performance change and ALFF change in the precuneus while a negative correlation was found in the bilateral orbitofrontal cortices (OFCs) and right medial frontal cortex (MFC). The ALFF changes normalised with the WM performance improvement post-operatively. The FPN activity in the right OFC was also increased pre-operatively. Partial correlation analysis revealed a significant correlation between WM performance and right OFC activity controlled for right FPN activity.
Conclusions
The abnormal activity of the OFCs and MFC that is not originating from the synchronous intrinsic network activity, together with the decreased activity of the central node of the DMN, could lead to cognitive impairment in SIH that is reversible through restoration of the cerebrospinal fluid.
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Hansen, E. K., Guo, S., Ashina, M., Olesen, J., 2015-09-30 06:50:45 AM
Background
A model for the testing of novel antimigraine drugs should ideally use healthy volunteers for ease of recruiting. Cilostazol provokes headache in healthy volunteers with some migraine features such as pulsating pain quality and aggravation by physical activity. Therefore, this headache might respond to sumatriptan, a requirement for validation. The hypothesis of the present study was that sumatriptan but not placebo is effective in cilostazol-induced headache in healthy individuals.
Methods
In a double-blind, randomized, cross-over design, 30 healthy volunteers of both sexes received cilostazol 200 mg on two separate days, each day followed by oral self-administered placebo or sumatriptan 50 mg. Headache response and accompanying symptoms were registered in a questionnaire by the participants themselves.
Results
Cilostazol induced a reproducible headache in 90% of the participants. The headache had several migraine-like features in most individuals. Median peak headache score was 2 on the sumatriptan day and 3 on the placebo day (p = 0.17). There was no reduction in headache intensity two hours after sumatriptan (p = 0.97) and difference in AUC 0 to four hours between two experimental days was not significant (p = 0.18). On the placebo day eight participants took rescue medication compared to 3 on the sumatriptan day (p = 0.13).
Conclusion
Despite similarities with migraine headache, cilostazol-induced headache in healthy volunteers does not respond to sumatriptan.
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Ho, T. W., Ho, A. P., Ge, Y., Assaid, C., Gottwald, R., MacGregor, E. A., Mannix, L. K., van Oosterhout, W. P., Koppenhaver, J., Lines, C., Ferrari, M. D., Michelson, D., 2015-09-30 06:50:45 AM
Aim
The aim of this article is to evaluate the safety and efficacy of perimenstrual telcagepant, a CGRP receptor antagonist, for headache prophylaxis.
Methods
We conducted a randomized, double-blind, placebo-controlled, six-month trial in women with migraine for ≥3 months who experienced perimenstrual headaches. Women were randomized to telcagepant 140 mg or placebo (2:1 ratio) for seven consecutive days perimenstrually. Safety was assessed by adverse events and laboratory tests. The primary efficacy endpoint was mean monthly headache days in the subset of women reporting perimenstrual migraine (–2 days to +3 days of menses onset) and ≥5 moderate or severe migraines per month prior to entering the trial.
Results
Telcagepant was generally well tolerated: 66/2660 (2.5%) on telcagepant and 36/1326 (2.7%) on placebo discontinued because of a clinical adverse event. The percentages of patients with clinical adverse events, laboratory adverse events, or discontinuation because of a laboratory adverse event were also similar between treatments. Alanine aminotransferase elevations ≥3x normal occurred in 0.6% of women on telcagepant and 0.4% on placebo. Three women on telcagepant vs none on placebo had alanine aminotransferase elevations ≥8xnormal. In the efficacy subset there was no significant effect of telcagepant (n = 887) vs placebo (n = 447) in mean monthly headache days (treatment difference –0.5 day (95% CI: –1.1, 0.1)). However, telcagepant was associated with a reduction in on-drug headache days (treatment difference –0.4 day (95% CI: –0.5, –0.2), nominal p < 0.001).
Conclusions
Telcagepant 140 mg taken perimenstrually for seven days was generally well tolerated, but was associated with transaminase elevations. Telcagepant did not reduce monthly headache frequency, but did reduce perimenstrual headaches.
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Tedeschi, G., Russo, A., Conte, F., Corbo, D., Caiazzo, G., Giordano, A., Conforti, R., Esposito, F., Tessitore, A., 2015-09-30 06:50:45 AM
Objective
To evaluate the resting-state visual network functional connectivity in patients with migraine with aura and migraine without aura during the interictal period.
Population and methods
Using resting-state functional magnetic resonance imaging, the resting-state visual network integrity was investigated in 20 patients with migraine with aura, 20 age- and sex-matched patients with migraine without aura and 20 healthy controls. Voxel-based morphometry and diffusion tensor imaging were used to assess whether between-groups differences in functional connectivity were dependent on structural or microstructural changes.
Results
Resting-state functional magnetic resonance imaging data showed that patients with migraine with aura, compared to both patients with migraine without aura and healthy controls, had a significant increased functional connectivity in the right lingual gyrus within the resting-state visual network (p < 0.05, cluster-level corrected). This abnormal resting-state visual network functional connectivity was observed in the absence of structural or microstructural abnormalities and was not related to migraine severity.
Conclusions
Our imaging data revealed that patients with migraine with aura exhibit an altered resting-state visual network connectivity. These results support the hypothesis of an extrastriate cortex involvement, centred in the lingual gyrus, a brain region related to mechanisms underlying the initiation and propagation of the migraine aura. This resting-state functional magnetic resonance imaging finding may represent a functional biomarker that could differentiate patients experiencing the aura phenomenon from patients with migraine without aura, even between migraine attacks.
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Bertolotto, A., Malentacchi, M., Capobianco, M., di Sapio, A., Malucchi, S., Motuzova, Y., Pulizzi, A., Berchialla, P., Sperli, F., 2015-09-30 06:50:45 AM
Objectives
The objectives of this article are to test the feasibility of lumbar puncture (LP) using 25-gauge (G) needles in daily neurological practice and to compare the risk of post-dural puncture headache (PDPH) with four types of needles.
Methods
In a prospective rater-blind study, pros and cons of four different LP needles, the 20G Quincke (20Q), 22G Sprotte (22S), 25G Whitacre (25W) and 25G Sprotte (25S), were evaluated in 394 LPs performed by seven neurologists. The neurologist performing the LP recorded the type and size of needle, intensity of pain, safety, time of the procedure and failure or success. Between five and 15 days later another neurologist, blind to the type of needle used, completed an ad-hoc questionnaire for PDPH.
Results
PDPH developed in 35.9% patients when using a 20Q needle, and in 12.9%, 6.8% and 1.6%, respectively, when using a 22S, 25W or 25S needle. The difference in incidence of PDPH following LP performed with the 20Q needle and the 25S or 22S was statistically significant (p < 0.001 and p = 0.008, respectively) and it approached significance when comparing the 25S and 25W (p = 0.06). As 25W and 25S needles need CSF aspiration, LP requires more time and skill. Pain caused by LP was similar with the four needles.
Conclusion
The use of the 25S needle in diagnostic LP reduces the frequency and severity of PDPH.
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Di Lorenzo, C., Coppola, G., Di Lorenzo, G., Bracaglia, M., Rossi, P., Pierelli, F., 2015-09-30 06:50:45 AM
Background
Cluster headache (CH) patients often receive unsatisfactory treatment and may explore illicit substances as alternatives. We aimed to explore this use of illicit drugs for CH treatment.
Methods
We invited CH patients from an Internet-based self-help group to complete a questionnaire regarding their therapeutic use of illicit substances.
Results
Of the 54 respondents, 29 were classified as chronic and 39 were drug-resistant cases. Fifty patients had previously tried subcutaneous sumatriptan, 40 had tried O2, and 48 had tried at least one prophylactic treatment. All 54 patients specified that they were dissatisfied with conventional treatments. Thirty-four patients had used cannabinoids, 13 cocaine, 8 heroin, 18 psilocybin, 12 lysergic acid amide (LSA), and 4 lysergic acid diethylamide (LSD).
Discussion
Some patients with intractable CH decided to try illicit drugs concomitantly with cessation of medical care. Most of these patients found suggestions for illicit drug use on the Internet. Many patients seemed to underestimate the judicial consequences of, and had an overestimated confidence in the safety of, such illicit treatments. Physicians are often not informed by patients of their choice to use illicit drugs. This leads to questions regarding the true nature of the physician-patient relationship among dissatisfied CH patients.
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Pijpers, J., Louter, M., de Bruin, M., van Zwet, E., Zitman, F., Ferrari, M., Terwindt, G., 2015-09-30 06:50:45 AM
Aim
The aim of this article is to determine whether support by a headache nurse in the treatment of medication-overuse headache (MOH) increases successful withdrawal, and to study determinants of response to withdrawal therapy.
Methods
A retrospective, controlled follow-up study was performed with 416 MOH patients. All patients were treated with outpatient withdrawal therapy, with two treatment arms: with or without the support of a specialised headache nurse. The outcome measures were: i) successful withdrawal, defined as discontinuation of all headache medication according to the study protocol; and ii) the responder rate, defined as the percentage of patients with ≥50% reduction in headache days after successful withdrawal and iii) relative reduction in headache days after successful withdrawal.
Results
Successful withdrawal percentages were significantly higher in the group supported by the headache nurse than in the group without support (73.1% vs. 60.7%; p = 0.008), which was confirmed in multivariate analysis (OR 1.73, 95% CI 1.11–2.71, p = 0.016). Support by a headache nurse was not associated with response. The underlying primary headache diagnosis, determined after withdrawal, was significantly correlated with response.
Conclusion
The support by a headache nurse results in an increased adherence to detoxification.
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Hansen, J. M., Larsen, V. A., Scheie, D., Perry, A., Skjoth-Rasmussen, J., 2015-09-30 06:50:45 AM
A 17-year-old female with migraine with aura complained of fatigue and was diagnosed with anemia. Three years later, changes in her headache pattern prompted hospital referral. Brain MRI showed a bi-lobed extra-axial intracerebral tumor encroaching both parieto-occipital regions. The resection specimen yielded a rare diagnosis of primary intracranial angiomatoid fibrous histiocytoma (AFH). Tumor removal resulted in cessation of her migraine and anemia. AFH may cause systemic symptoms – in this case fatigue and anemia – long before focal neurological symptoms are present. This is the first report of an intracranial AFH presenting as migraine with visual aura and anemia.
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Takizawa, T., Shibata, M., Fujiwara, H., Shimizu, T., Momoshima, S., Suzuki, N., 2015-09-30 06:50:45 AM
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Honningsvag, L.-M., Hagen, K., Haberg, A., Stovner, L. J., Linde, M., 2015-09-30 06:50:45 AM
Background
Most studies on intracranial abnormalities among headache sufferers were performed in selected clinical populations. The aim of this study was to evaluate the relationship between intracranial abnormalities and headache among middle-aged adults in the general population.
Methods
Participants in a large epidemiological study (the HUNT 3 study; 2006–2008) who answered a headache questionnaire and participated in a population-based imaging study of the head (HUNT MRI; 2007–2009) were included (n = 864; age, 50–65 at enrollment). Based on the responses to the HUNT 3 questionnaire, respondents were categorized as having migraine, tension-type headache, or unclassified headache. Logistic regression was used to compare the occurrence of intracranial abnormalities between groups.
Results
Intracranial abnormalities were more common in headache sufferers than in headache-free individuals (29% vs. 22%, respectively; p = 0.041). Adjusted multivariate analyses revealed that those with tension-type headache had higher odds of having minor abnormalities (odds ratio, 2.13; 95% confidence interval = 1.18–3.85). This association disappeared when those with only white matter hyperintensities were removed from the analysis.
Conclusions
Headache sufferers had increased odds of minor intracranial abnormalities. The increased odds were primarily related to the presence of white matter hyperintensities.
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Fang, L., Jingjing, L., Ying, S., Lan, M., Tao, W., Nan, J., 2015-09-30 06:50:45 AM
Background
Sphenopalatine ganglion percutaneous radiofrequency thermocoagulation treatment can improve the symptoms of cluster headaches to some extent. However, as an ablation treatment, radiofrequency thermocoagulation treatment also has side effects.
Objective
To preliminarily evaluate the efficacy and safety of a non-ablative computerized tomography-guided pulsed radiofrequency treatment of sphenopalatine ganglion in patients with refractory cluster headaches.
Methods
We included and analysed 16 consecutive cluster headache patients who failed to respond to conservative therapy from the Pain Management Center at the Beijing Tiantan Hospital between April 2012 and September 2013 treated with pulsed radiofrequency treatment of sphenopalatine ganglion.
Results
Eleven of 13 episodic cluster headaches patients and one of three chronic cluster headaches patient were completely relieved of the headache within an average of 6.3 ± 6.0 days following the treatment. Two episodic cluster headache patients and two chronic cluster headache patients showed no pain relief following the treatment. The mean follow-up time was 17.0 ± 5.5 months. All patients enrolled in this study showed no treatment-related side effects or complications.
Conclusion
Our data show that patients with refractory episodic cluster headaches were quickly, effectively and safely relieved from the cluster period after computerized tomography-guided pulsed radiofrequency treatment of sphenopalatine ganglion, suggesting that it may be a therapeutic option if conservative treatments fail.
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Niddam, D. M., Lai, K.-L., Fuh, J.-L., Chuang, C.-Y. N., Chen, W.-T., Wang, S.-J., 2015-09-30 06:50:45 AM
Background
Migraine with visual aura (MA) is associated with distinct visual disturbances preceding migraine attacks, but shares other visual deficits in between attacks with migraine without aura (MO). Here, we seek to determine if abnormalities specific to interictal MA patients exist in functional brain connectivity of intrinsic cognitive networks. In particular, these networks are involved in top-down modulation of visual processing.
Methods
Using resting-state functional magnetic resonance imaging, whole-brain functional connectivity maps were derived from seeds placed in the anterior insula and the middle frontal gyrus, key nodes of the salience and dorsal attention networks, respectively. Twenty-six interictal MA patients were compared with 26 matched MO patients and 26 healthy matched controls.
Results
The major findings were: connectivity between the anterior insula and occipital areas, including area V3A, was reduced in MA but not in MO. Connectivity changes between the anterior insula and occipital areas further correlated with the headache severity in MA only.
Conclusions
The unique pattern of connectivity changes found in interictal MA patients involved area V3A, an area previously implicated in aura generation. Hypoconnectivity to this and other occipital regions may either represent a compensatory response to occipital dysfunctions or predispose MA patients to the development of aura.
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Abu Bakar, N., Tanprawate, S., Lambru, G., Torkamani, M., Jahanshahi, M., Matharu, M., 2015-09-30 06:50:45 AM
Background
Health-related quality of life (HRQoL) is emerging as an important element of clinical research in primary headache disorders, allowing a measure of the impact of headache on patients' well-being and daily life. A better understanding of this may contribute to improved resource allocations and treatment approaches.
Objective
The objective of this study is to review available data on HRQoL in primary headache disorders and identify any influencing factors.
Methods
Database searches including MEDLINE, PsycINFO and EMBASE were performed. Studies that investigated HRQoL in patients with primary headache disorders were included and reviewed. Trials that evaluated the efficacy of medications or interventions were excluded.
Results
A total of 80 articles were included in the review. Both physical and emotional/mental aspects of HRQoL were impaired across headache subtypes, although the extent varied depending on headache type. A number of factors influencing HRQoL were also identified.
Conclusion
This narrative review suggests that headache, particularly in its chronic form, has a great impact on HRQoL. Clinical practice should not solely focus on pain alleviation but rather adopt routine assessment of HRQoL. Furthermore, identification and management of associated psychological comorbidities, which can significantly influence HRQoL in headache sufferers, are essential for optimal clinical management.
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Takizawa, T., Shibata, M., Kayama, Y., Toriumi, H., Ebine, T., Koh, A., Shimizu, T., Suzuki, N., 2015-09-30 06:50:45 AM
Introduction
Cortical spreading depression (CSD) has recently been shown to induce the release of the nuclear protein termed high-mobility group box 1 from neurons, causing activation of the trigeminovascular system. Here, we explored the effects of single and multiple cortical spreading depression inductions on high-mobility group box 1 (HMGB1) transcriptional activity relative to high-mobility group box 1 protein expression levels and intracellular localization in cortical neurons and astrocytes.
Methods
Single or multiple cortical spreading depression inductions were achieved by KCl application to the mouse cerebral cortex. The animals were sacrificed at 30 minutes, 3 hours and 24 hours after cortical spreading depression induction. High-mobility group box 1 expression levels were explored with in situ hybridization, Western blotting and immunostaining.
Results
Cortical spreading depression up-regulated high-mobility group box 1 transcriptional activity in neurons at 3 hours in a manner that was dependent on the number of cortical spreading depression inductions. At 24 hours, thehigh-mobility group box 1 transcriptional activity had returned to basal levels. Cortical spreading depression induced a reduction in high-mobility group box 1 protein expression at 3 hours, which was also dependent on the number of cortical spreading depression inductions. Following cortical spreading depression, the release of high-mobility group box 1 from the nucleus was observed in a small proportion of neurons, but not in astrocytes.
Conclusion
Cortical spreading depression induced translocation of high-mobility group box 1 from neuronal nuclei, driving transcriptional up-regulation of high-mobility group box 1 to maintain protein levels.
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Altiokka, O., Mutluay, B., Koksal, A., Ciftci-Kavaklioglu, B., Ozturk, M., Altunkaynak, Y., Baybas, S., Soysal, A., 2015-09-30 06:50:45 AM
Objective
To investigate which part of the autonomic system is mainly involved and assess the sensitivity of face sympathetic skin response in cluster headache.
Material and methods
The study sample consisted of 19 drug-free cluster headache patients (16 males, three females) and 19 healthy volunteers. Demographic features and pain characteristics were thoroughly identified. Dysautonomic symptoms were evaluated during attack and remission periods of cluster headache patients. Orthostatic hypotension, R-R interval variation and sympathetic skin responses obtained from the face and four extremities were evaluated and the sensitivity of face sympathetic skin responses was assessed in contrast to extremity sympathetic skin responses.
Results
All sympathetic skin responses of face and extremities could be obtained during attack and remission periods. On the symptomatic side, mean latency of face sympathetic skin responses was longer compared to the asymptomatic side and controls (p = 0.02, p = 0.004). There were no differences in latency or amplitude of extremity sympathetic skin responses between symptomatic and asymptomatic sides and controls. No significant relationship was determined between sympathetic skin responses, R-R interval variation, orthostatic hypotension and cluster headache clinical features.
Conclusion
Sympathetic hypoactivity of the face seems to predominate the pathophysiology of cluster headache. Face sympathetic skin responses might be more sensitive compared to extremity sympathetic skin response in demonstrating dysautonomic symptoms in cluster headache patients.
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de Coo, I. F., Wilbrink, L. A., Haan, J., 2015-09-30 06:50:45 AM
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Madsen, B. K., Sogaard, K., Andersen, L. L., Skotte, J. H., Jensen, R. H., 2015-09-30 06:50:45 AM
Introduction
Tension-type headache (TTH) is highly prevalent in the general population, and it is characterized by increased muscle tenderness with increasing headache frequency and intensity.
Aim
The aim of this case-control study was to compare muscle strength in neck and shoulder muscles in TTH patients and healthy controls by examining maximal voluntary isometric contraction (MVC) during shoulder abduction, neck flexion and extension as well as the extension/flexion strength ratio of the neck.
Methods
Sixty TTH patients and 30 sex- and age-matched healthy controls were included. Patients were included if they had TTH ≥8 days per month. The MVC neck extensor and flexor muscles were tested with the participant seated upright. MVC shoulder abduction was tested with the individual lying supine.
Results
Compared to controls TTH patients had significantly weaker muscle strength in neck extension (p = 0.02), resulting in a significantly lower extension/flexion moment ratio (p = 0.03). TTH patients also showed a tendency toward significantly lower muscle strength in shoulder abduction (p = 0.05). Among the 60 TTH patients, 25 had frequent episodic TTH (FETTH), and 35 had chronic TTH (CTTH).
Conclusion
Patients with TTH exhibited decreased muscle strength in the neck extensor muscles, inducing a reduced cervical extension/flexion ratio compared to healthy people.
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Westergaard, M. L., Glumer, C., Hansen, E. H., Jensen, R. H., 2015-09-30 06:50:45 AM
Aim
This cross-sectional study investigated associations between chronic headache (CH) with and without medication overuse, healthy lifestyle behaviour, and stress.
Methods
Questionnaires were sent to 129,150 adults. Those with headache ≥15 days per month for three months were classified as having CH then further described as having medication-overuse headache (MOH) or CH without medication overuse. Associations between headache and daily smoking, physical inactivity, obesity, excessive drinking, illicit drug use, and high stress were analysed by logistic regression.
Results
CH with and without medication overuse (prevalence 1.8% and 1.6%, respectively) had strong, graded associations with stress. Associations with daily smoking, physical inactivity, and obesity were significant only for MOH. Odds for MOH were highest among people who had all three factors compared to those who had none (OR 2.8 in women and 5.1 in men). High stress plus any of these three factors had synergistic effects in MOH but not clearly in those who had CH without overuse. Associations between CH subtypes and excessive drinking or illicit drug use were not statistically significant.
Conclusion
Results suggest strong links between healthy lifestyle behaviour and stress in MOH. Stress reduction and promoting healthy behaviour are highly relevant in MOH management.
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Messina, R., Rocca, M. A., Colombo, B., Pagani, E., Falini, A., Comi, G., Filippi, M., 2015-09-30 06:50:45 AM
Background
Diffusion tensor (DT) magnetic resonance imaging (MRI) provides several quantities with the potential to disclose white matter (WM) microstructural abnormalities. We explored alterations of WM architecture in pediatric migraine patients using DT MRI and two different methods of analysis.
Methods
Dual-echo and DT MRI scans were acquired from 15 pediatric migraine patients and 15 age-matched controls. Whole-brain voxel-wise comparisons of WM DT MRI abnormalities were performed using tract-based-spatial-statistics (TBSS). A DT probabilistic tractography analysis was also run.
Results
Both TBSS and DT tractography analysis showed that, compared to controls, pediatric migraine patients had significant lower mean (MD), axial (AD) and radial (RD) diffusivity of WM tracts located in the brainstem, thalamus and fronto-temporo-occipital lobes, bilaterally. Patients also experienced increased fractional anisotropy (FA) of the optic radiations. No correlation was found between WM tract abnormalities and disease duration and attack frequency.
Conclusions
Pediatric migraine patients harbor diffuse brain WM microstructural abnormalities. High FA and low MD, AD and RD in these patients might be explained by repeated neuronal activation, which may lead to cell swelling and stimulate activity-dependent myelin-modulation, or by increased fiber and dendritic densities. Both these mechanisms might reflect a hyperexcitability of the brain in migraineurs.
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Pozo-Rosich, P., Storer, R., Charbit, A., Goadsby, P., 2015-09-30 06:50:45 AM
Background
Calcitonin gene-related peptide (CGRP) receptor antagonism is an approach to migraine therapy. The locus of action of antimigraine treatment is not resolved. The objective was to investigate CGRP receptors in the ventrolateral periaqueductal gray (vlPAG) involved in the modulation of trigeminovascular nociception by descending influences on neurotransmission.
Methods
The presence of calcitonin receptor-like receptor (CLR) and receptor activity modifying protein 1 (RAMP1), which form functional CGRP receptors, was investigated. CGRP and its receptor antagonists, olcegepant and CGRP (8–37), were microinjected into the vlPAG while changes of neural responses in the trigeminocervical complex (TCC) were monitored.
Results
Immunoreactivity indicated the presence of functional CGRP receptor components in the vlPAG and adjacent mesencephalic trigeminal nucleus. Inhibition of TCC responses to stimulation of dural afferents and ophthalmic cutaneous receptive fields after microinjection of bicuculline into vlPAG indicated a connection between the vlPAG and TCC neurons. CGRP facilitated these TCC responses, whereas olcegepant and CGRP (8–37) decreased them.
Conclusions
CGRP and its receptor antagonists act on neurons in the region of vlPAG to influence nociceptive transmission in the TCC. This suggests CGRP receptor antagonists may act at loci outside of the TCC and reinforces the concept of migraine as a disorder of the brain.
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Pareja, J. A., Casanova, I., Arbex, A., Cuadrado, M. L., 2015-09-30 06:50:45 AM
Introduction
The infratrochlear nerve supplies the medial aspect of the upper eyelid, the superolateral aspect of the nose and the lacrimal caruncle. This nerve may contribute to the pain stemming from the trochlea, but infratrochlear neuralgia has not been identified as a specific cause of pain.
Methods
Over a 10-year period we have been recruiting patients with pain in the internal angle of the orbit that did not show features of trochlear pain.
Results
Seven patients (six female, one male; mean age, 46.1 ± 18.9) presented with pain in the territory of the infratrochlear nerve. The pain appeared in the internal angle of the orbit and upper eyelid (n = 3), the superolateral aspect of the nose (n = 3), or the lacrimal caruncle (n = 1). All patients had a paroxysmal pain, with the attacks lasting five to 30 seconds. Pain attacks were mostly spontaneous, but two patients had triggers. Between attacks, all patients had local allodynia. Pain did not increase with vertical eye movements. Six patients were treated with gabapentin with complete response, and one patient experienced long-lasting relief with an anesthetic blockade of the infratrochlear nerve.
Conclusion
Infratrochlear neuralgia should be considered as a possible cause of pain in the internal angle of the orbit.
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Nguyen, B. N., McKendrick, A. M., Vingrys, A. J., 2015-09-30 06:50:45 AM
Background
People with migraine show increased surround suppression of perceived contrast, a perceptual analogue of centre-surround antagonistic interactions in visual cortex. A proposed mechanism is that cortical 'hyperexcitability' or 'hyperresponsivity', a prominent theory in the migraine literature, drives abnormal excitatory-inhibitory balance to give increased local inhibition. The purpose of this cross-sectional study was to determine whether cortical hyperresponsivity and excitatory-inhibitory imbalance manifests in the visual cortical response of migraine sufferers.
Methods
Interictal steady-state visual evoked potentials (VEPs) in response to 0 to 97% contrast were recorded in 30 migraine participants (15 without aura, 15 with aura) and 21 non-headache controls. Monotonicity indices were calculated to determine response saturation or supersaturation. Contrast gain was modelled with a modified saturating hyperbolic function to allow for variation in excitation and inhibition.
Results
A greater proportion of migraine participants (43%) than controls (14%) exhibited significant VEP supersaturation at high contrast, based on monotonicity index (chi-square, p = 0.028). Supersaturation was also evident by the trend for greater suppressive exponent values in migraine compared to control individuals (Mann-Whitney rank sum, p = 0.075).
Conclusions
Supersaturation in migraine is consistent with excess excitation (hyperresponsivity) driving increased network inhibition and provides support for excitatory-inhibitory imbalance as a pathophysiological disturbance in migraine.
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Barloese, M., Brinth, L., Mehlsen, J., Jennum, P., Lundberg, H. I. S., Jensen, R., 2015-09-30 06:50:45 AM
Background
Cluster headache (CH) is a disabling headache disorder with chronobiological features. The posterior hypothalamus is involved in CH pathophysiology and is a hub for autonomic control. We studied autonomic response to the head-up tilt table test (HUT) including heart rate variability (HRV) in CH patients and compared results to healthy controls.
Methods and materials
Twenty-seven episodic and chronic CH patients and an equal number of age-, sex- and BMI-matched controls were included. We analyzed responses to HUT in the time and frequency domain and by non-linear analysis.
Results
CH patients have normal cardiovascular responses compared to controls but increased blood pressure. In the frequency analysis CH patients had a smaller change in the normalized low- (LF) (2.89 vs. 13.38, p < 0.05) and high-frequency (HF) (–2.86 vs. –13.38, p < 0.05) components as well as the LF/HF ratio (0.81 vs. 2.62, p < 0.05) in response to tilt. In the Poincaré plot, the change in ratio between long- and short-term variation was lower in patients (SD1/SD2, –0.05 vs. –0.17, p < 0.05).
Conclusions
CH patients show decreased autonomic response to HUT compared to healthy controls. This can be interpreted as dysregulation in the posterior hypothalamus and supports a theory of central autonomic mechanisms involvement in CH.
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Kageyama, T., Isohisa, A., Mori, N., Suenaga, T., 2015-09-30 06:50:45 AM
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Sillanpaa, M., Saarinen, M., 2015-09-30 06:50:45 AM
Purpose
To explore the association between infantile colic and adolescent migraine.
Method
In a randomized general population sample, families expecting their first child were prospectively followed for infantile colic and adolescent migraine.
Results
Colic was diagnosed in 160 (13%) of 1267 infants until the age of 3 months. Migraine was ascertained in 129 (16%) of 787 adolescents at age 18 years. History of infantile colic was identified in 96 (12%) of 787 adolescents and no such history in 658 (88%) of 787 adolescents. Migraine was present in 22 (23%)/96 adolescents who had a history of infantile colic, but in only 74 (11%)/658 ones who had no such history. Of the 22 adolescents, 14 (64%) had migraine without aura and eight (36%) had migraine with aura. Infants with colic had an almost three-fold risk (risk ratio 2.8, 95% confidence interval 1.2–6.5) for adolescent migraine without aura, but no increased risk for migraine with aura (0.8, 0.3–2.2).
Discussion and conclusions
Infantile colic seems to be associated with an increased risk for migraine without aura, but not for migraine with aura. Whether infantile colic per se is a type of infantile migraine or an antecedent of future migraine remains to be answered by further research.
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Gelfand, A. A., Fullerton, H. J., Jacobson, A., Sidney, S., Goadsby, P. J., Kurth, T., Pressman, A., 2015-09-30 06:50:45 AM
Importance
Our understanding of risk factors for childhood stroke is incomplete. In adults, migraine with aura is associated with a two-fold increase in ischemic stroke risk.
Objective
In this cohort study we examine the association between migraine and stroke among children in Kaiser Permanente Northern California (KPNC).
Design, setting, and participants
Children ages 2–17 years who were members of KPNC for ≥6 months between 1997 and 2007 were included. Migraine cohort members had one or more of: an ICD-9 code for migraine, migraine listed as a significant health problem, or a prescription for a migraine-specific medication. The comparison group was children with no evidence of headache.
Main outcome measures
Main outcome measures included stroke incidence rates and incidence rate ratios (IR).
Results
Among the 1,566,952 children within KPNC during the study period, 88,164 had migraine, and 1,323,142 had no evidence of headache. Eight migraineurs had a stroke (three (38%) hemorrhagic; five (63%) ischemic). Eighty strokes occurred in children without headache (53 (66%) hemorrhagic; 27 (34%) ischemic). The ischemic stroke incidence rate was 0.9/100,000 person-years in migraineurs vs. 0.4/100,000 person-years in those without headache; IR 2.0 (95% CI 0.8–5.2). A post-hoc analysis of adolescents (12–17 years) showed an increased risk of ischemic stroke among those with migraine; IR 3.4 (95% CI 1.2–9.5). The hemorrhagic stroke incidence rate was 0.5/100,000 person-years in migraineurs and 0.9/100,000 person-years in those without headache; IR 0.6 (95% CI 0.2–2.0).
Conclusions
There was no statistically significant increase in hemorrhagic or ischemic stroke risk in pediatric migraineurs in this cohort study. A post-hoc analysis found that ischemic stroke risk was significantly elevated in adolescents with migraine. Future studies should focus on identifying risk factors for ischemic stroke among adolescent migraineurs. Based on adult data, we recommend that migraine aura status should be studied as a possible risk factor for ischemic stroke among adolescent migraineurs.
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Vetvik, K. G., Benth, J. Šaltyte, MacGregor, E. A., Lundqvist, C., Russell, M. B., 2015-09-30 06:50:45 AM
Objective
The objective of this article is to compare clinical characteristics of menstrual and non-menstrual attacks of migraine without aura (MO), prospectively recorded in a headache diary, by women with and without a diagnosis of menstrual migraine without aura (MM) according to the International Classification of Headache Disorders (ICHD).
Material and methods
A total of 237 women from the general population with self-reported migraine in ≥50% of their menstrual periods were interviewed and classified by a physician according to the criteria of the ICHD II. Subsequently, all participants were instructed to complete a prospective headache diary for at least three menstrual cycles. Clinical characteristics of menstrual and non-menstrual attacks of MO were compared by a regression model for repeated measurements.
Results
In total, 123 (52%) women completed the diary. In the 56 women who were prospectively diagnosed with MM by diary, the menstrual MO-attacks were longer (on average 10.65 hours, 99% CI 3.17–18.12) and more frequently accompanied by severe nausea (OR 2.14, 99% CI 1.20–3.84) than non-menstrual MO-attacks. No significant differences between menstrual and non-menstrual MO-attacks were found among women with MO, but no MM.
Conclusion
In women from the general population, menstrual MO-attacks differ from non-menstrual attacks only in women who fulfil the ICHD criteria for MM.
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Mesa-Jimenez, J. A., Lozano-Lopez, C., Angulo-Diaz-Parreno, S., Rodriguez-Fernandez, A. L., De-la-Hoz-Aizpurua, J. L., Fernandez-de-las-Penas, C., 2015-09-30 06:50:45 AM
Background
Manual therapies are generally requested by patients with tension type headache.
Objective
To compare the efficacy of multimodal manual therapy vs. pharmacological care for the management of tension type headache pain by conducting a meta-analysis of randomized controlled trials.
Methods
PubMed, MEDLINE, EMBASE, AMED, CINAHL, EBSCO, Cochrane Database of Systematic Reviews, Cochrane Collaboration Trials Register, PEDro and SCOPUS were searched from their inception until June 2014. All randomized controlled trials comparing any manual therapy vs. medication care for treating tension type headache adults were included. Data were extracted and methodological quality assessed independently by two reviewers. We pooled headache frequency as the main outcome and also intensity and duration. The weighted mean difference between manual therapy and pharmacological care was used to determine effect sizes.
Results
Five randomized controlled trials met our inclusion criteria and were included in the meta-analysis. Pooled analyses found that manual therapies were more effective than pharmacological care in reducing frequency (weighted mean difference –0.8036, 95% confidence interval –1.66 to –0.44; three trials), intensity (weighted mean difference –0.5974, 95% confidence interval –0.8875 to –0.3073; five trials) and duration (weighted mean difference –0.5558, 95% confidence interval –0.9124 to –0.1992; three trials) of the headache immediately after treatment. No differences were found at longer follow-up for headache intensity (weighted mean difference –0.3498, 95% confidence interval –1.106 to 0.407; three trials).
Conclusion
Manual therapies were associated with moderate effectiveness at short term, but similar effectiveness at longer follow-up for reducing headache frequency, intensity and duration in tension type headache than pharmacological medical drug care. However, due to the heterogeneity of the interventions, these results should be considered with caution at this stage.
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Schulte, L., May, A., 2015-09-30 06:50:45 AM
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Ambrosini, A., D'Alessio, C., Magis, D., Schoenen, J., 2015-09-30 06:50:45 AM
Background
Migraine is a highly prevalent neurological disorders and a major individual and societal burden. Migraine is not curable at the present time, but it is amenable to acute symptomatic and preventive pharmacotherapies.
Summary
Since the latter are frequently unsatisfactory, other treatment strategies have been used or are being explored. In particular, interventions targeting pericranial nerves are now part of the migraine armamentarium. We will critically review some of them, such as invasive and noninvasive neurostimulation, therapeutic blocks and surgical decompressions.
Conclusions
Although current knowledge on migraine pathophysiology suggests a central nervous system dysfunction, there is some evidence that interventions targeting peripheral nerves are able to modulate neuronal circuits involved in pain control and that they could be useful in some selected patients. Larger, well-designed and comparative trials are needed to appraise the respective advantages, disadvantages and indications of most interventions discussed here.
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Gelfand, A. A., 2015-09-30 06:50:45 AM
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Pedersen, S. H., Ramachandran, R., Amrutkar, D. V., Petersen, S., Olesen, J., Jansen-Olesen, I., 2015-09-30 06:50:45 AM
Background
Migraine patients develop attacks several hours after intravenous infusion of glyceryl trinitrate. Due to the short half-life of nitric oxide, this delayed migraine cannot be caused by a direct action of nitric oxide derived from glyceryl trinitrate. The involvement of meningeal inflammation and dural mast cell degranulation is supported by the effectiveness of prednisolone on glyceryl trinitrate-induced delayed headache.
Methods
Using a newly developed rat model mimicking the human glyceryl trinitrate headache model, we have investigated the occurrence of dural mast cell degranulation after a clinically relevant dose of glyceryl trinitrate.
Results
A 6-fold increase in degranulation was observed starting at 2 hours after glyceryl trinitrate infusion. Interestingly, pre-treatment with the effective anti-migraine substances L-nitro-arginine methyl ester and sumatriptan prevented glyceryl trinitrate-induced mast cell degranulation whereas the calcitonin gene-related peptide-receptor antagonist olcegepant and the substance P receptor antagonist L-733,060 did not affect mast cell degranulation. However, topical application of two different nitric oxide donors did not cause mast cell degranulation ex vivo.
Conclusions
Direct application of an exogenous nitric oxide donor on dural mast cells does not cause mast cell degranulationex vivo. In vivo application of the nitric oxide donor glyceryl trinitrate leads to a prominent level of degranulation via a yet unknown mechanism. This effect can be completely blocked by inhibition of the endogenous nitric oxide production and by 5-HT1B/1D receptor agonists but is unaffected by calcitonin gene-related peptide and substance P receptor antagonists.
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Kunkler, P. E., Zhang, L., Pellman, J. J., Oxford, G. S., Hurley, J. H., 2015-09-30 06:50:45 AM
Background
Air pollution is linked to increased emergency room visits for headache, and migraine patients frequently cite chemicals or odors as headache triggers, but the association between air pollutants and headache is not well understood. We previously reported that nasal administration of environmental irritants acutely increases meningeal blood flow via a TRPA1-dependent mechanism involving the trigeminovascular system. Here, we examine whether chronic environmental irritant exposure sensitizes the trigeminovascular system.
Methods
Male rats were exposed to acrolein, a TRPA1 agonist, or room air by inhalation for four days prior to meningeal blood flow measurements. Some animals were injected daily with a TRPA1 antagonist, AP-18, or vehicle prior to inhalation exposure. Trigeminal ganglia were isolated following blood flow measurements for immunocytochemistry and/or qPCR determination of TRPV1, TRPA1 and CGRP levels.
Results
Acrolein inhalation exposure potentiated blood flow responses both to TRPA1 and TRPV1 agonists compared to room air. Acrolein exposure did not alter TRPV1 or TRPA1 mRNA levels or TRPV1 or CGRP immunoreactive cell counts in the trigeminal ganglion. Acrolein sensitization of trigeminovascular responses to a TRPA1 agonist was attenuated by pre-treatment with AP-18.
Interpretation
These results suggest trigeminovascular sensitization as a mechanism for enhanced headache susceptibility after chemical exposure.
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Beams, J. L., Kline, M. T., Rozen, T. D., 2015-09-30 06:50:45 AM
Objective
The objective of this research is to describe novel procedural treatments for hemicrania continua that allow patients to remain off indomethacin.
Methods
Case reports are presented.
Results
We describe four distinct patients with indomethacin-responsive hemicrania continua who were unable to discontinue the use of indomethacin without headache recurrence. No other medications were effective for their syndrome. Secondary causes of headache were ruled out in each case. Each patient underwent diagnostic blockade of either the atlanto-axial joint, C2 dorsal root ganglion or sphenopalantine ganglion depending on their clinical examination and presence of cranial autonomic symptoms. A positive response led to a radiofrequency ablation of the C2 ventral ramus, C2 dorsal root ganglion or sphenopalantine ganglion, which provided headache relief in all case patients as complete as indomethacin. Long-term follow-up of these patients has shown that all have remained essentially headache free without the need for indomethacin. One patient has needed repeat radiofrequency procedures with consistent response.
Conclusion
Hemicrania continua is defined by its sensitivity to indomethacin but very few patients are able to discontinue the medication without headache recurrence. As the risks of chronic indomethacin use are substantial, alternative treatments are necessary to protect patient health. We are now able to suggest several radiofrequency ablation procedures as effective as indomethacin with long-term follow-up.
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Krogh, A.-B., Larsson, B., Linde, M., 2015-09-30 06:50:45 AM
Background
Headache is common in adolescents and affects schoolwork and relations with friends and family. In most previous epidemiological surveys, only the most bothersome headache has been documented. The aim was to determine headache prevalence not only taking into account the most bothersome headache, but also to compare characteristics of the most bothersome and less bothersome headaches, and to investigate headache-related disability.
Methods
A cross-sectional school-based study was conducted in which 493 representative adolescents aged 12–18 years were recruited by stratified cluster sampling and interviewed. Headache diagnosis was made according to the new classification system of the International Headache Society (ICHD-3 beta), and the Pediatric Migraine Disability Assessment (PedMIDAS) was used to evaluate disability.
Results
The one-year prevalence of any headache type, definite migraine, probable migraine and tension-type headache was 88%, 23%, 13% and 58%, respectively. The point prevalence of any headache was 38%. Nine percent of participants fulfilled criteria for more than one headache diagnosis. The most bothersome headache had a significantly longer duration (p < 0.001) and higher intensity (p < 0.001) than the less bothersome headache, but similar frequency (p = 0.86). Adolescents with headaches lost up to nine days of activity each year, implicating headache as a major health issue.
Conclusions
Headaches are very common and disabling among adolescents. The full extent of this health problem is better appreciated if inquiry is not limited to the most bothersome subtypes.
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Chong, C. D., Schwedt, T. J., 2015-09-30 06:50:45 AM
Background
Specific white-matter tract alterations in migraine remain to be elucidated. Using diffusion tensor imaging (DTI), this study investigated whether the integrity of white-matter tracts that underlie regions of the "pain matrix" is altered in migraine and interrogated whether the number of years lived with migraine modifies fibertract structure.
Methods
Global probabilistic tractography was used to assess the anterior thalamic radiations, the corticospinal tracts and the inferior longitudinal fasciculi in 23 adults with migraine and 18 healthy controls.
Results
Migraine patients show greater mean diffusivity (MD) in the left and right anterior thalamic radiations, the left corticospinal tract, and the right inferior longitudinal fasciculus tract. Migraine patients also show greater radial diffusivity (RD) in the left anterior thalamic radiations, the left corticospinal tract as well as the left and right inferior longitudinal fasciculus tracts. No group fractional anisotropy (FA) differences were identified for any tracts. Migraineurs showed a positive correlation between years lived with migraine and MD in the right anterior thalamic radiations (r = 0.517; p = 0.012) and the left corticospinal tract (r = 0.468; p = 0.024).
Conclusion
Results indicate that white-matter integrity is altered in migraine and that longer migraine history is positively correlated with greater alterations in tract integrity.
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Frishberg, B., 2015-09-30 06:50:45 AM
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Altıokka-Uzun, G., Tuzun, E., Ekizoğlu, E., Ulusoy, C., Yentur, S., Kurtuncu, M., Saruhan-Direskeneli, G., Baykan, B., 2015-09-30 06:50:45 AM
Objectives
The pathogenesis of idiopathic intracranial hypertension (IIH) is currently unknown and there are speculations about the contribution of some immunologic factors. The aim of this study is to investigate the presence of oligoclonal bands (OCBs) and cerebrospinal fluid (CSF) and/or serum cytokine levels in patients with IIH.
Methods
Patients fulfilling revised diagnostic criteria for IIH were included. Their demographic, clinical, ophthalmologic and laboratory features were examined. Serum and CSF samples were detected by isoelectric focusing and immunoblotting for OCBs. The samples of IIH patients and control groups were investigated by ELISA for cytokine levels.
Results
We detected OCBs in eight (30.77%) patients diagnosed with IIH. There were no other obvious clinical and laboratory differences of IIH profiles between the patients with and without OCBs, but frequency of vision loss was significantly higher in the group with OCBs in comparison to OCB negatives (p = 0.038). Patients with IIH had highly elevated TNF-α, IFN-, IL-4, IL-10, IL-12, IL-17 in their sera compared to patients with multiple sclerosis (MS) and healthy controls. Furthermore, all cytokines except TNF-α in the CSF were found significantly higher in IIH patients compared to MS controls.
Conclusion
The presence of OCBs and elevated cytokine levels in IIH patients may support an immunologic background in the pathophysiological pathway of this disorder.
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Callaghan, B. C., Kerber, K. A., Pace, R. J., Skolarus, L., Cooper, W., Burke, J. F., 2015-09-30 06:50:45 AM
Aims
The aim of this article is to determine the patient-level factors associated with headache neuroimaging in outpatient practice.
Methods
Using data from the 2007–2010 National Ambulatory Medical Care Surveys (NAMCS), we estimated headache neuroimaging utilization (cross-sectional). Multivariable logistic regression was used to explore associations between patient-level factors and neuroimaging utilization. A Markov model with Monte Carlo simulation was used to estimate neuroimaging utilization over time at the individual patient level.
Results
Migraine diagnoses (OR = 0.6, 95% CI 0.4–0.9) and chronic headaches (routine, chronic OR = 0.3, 95% CI 0.2–0.6; flare-up, chronic OR = 0.5, 95% CI 0.3–0.96) were associated with lower utilization, but even in these populations neuroimaging was ordered frequently. Red flags for intracranial pathology did not increase use of neuroimaging studies (OR = 1.4, 95% CI 0.95–2.2). Neurologist visits (OR = 1.7, 95% CI 0.99–2.9) and first visits to a practice (OR = 3.2, 95% CI 1.4–7.4) were associated with increased imaging. A patient with new migraine headaches has a 39% (95% CI 24–54%) chance of receiving a neuroimaging study after five years and a patient with a flare-up of chronic headaches has a 51% (32–68%) chance.
Conclusions
Neuroimaging is routinely ordered in outpatient headache patients including populations where guidelines specifically recommend against their use (migraines, chronic headaches, no red flags).
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Goulart, A. C., Santos, I. S., Lotufo, P. A., Bensenor, I. M., 2015-09-30 06:50:45 AM
Background
The relationship between cardiovascular risk factors (CVRF) and migraine is controversial and might be different in both genders. These associations were evaluated in Brazilian middle-aged men and women from the Longitudinal Study of Adult Health (ELSA-Brasil).
Methods
The cross-sectional relationship between our main outcome, which was migraine headache (definite, probable and overall), and CVRF was evaluated in the total sample and according to gender. We calculated frequencies and odds ratios (95% CI) for this relationship using binary and multinomial logistic regression analyses in crude, age-adjusted and multivariable models adjusted by potential confounders.
Results
Of 14,953 individuals who completed the data about headache and CVRF, the frequency of one-year migraine was of 29.5% (22.5% in women and 7.0% in men). In the multivariable-adjusted regression analyses, an inverse association between hypertension (OR, 0.53; 95% CI, 0.36–0.79), metabolic syndrome (OR, 0.65; 95% CI, 0.43–0.99) and definite migraine were confirmed for men, but not for women. In the opposite direction, a positive association between migraine headaches (definite, probable and overall) and dyslipidemia (overall migraine OR, 1.25; 95% CI, 1.13–1.38) was observed only for women, but not for men.
Conclusions
A gender influence on the relationship between migraine and CVRF was verified in the ELSA-Brasil.
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Smith, R. M., Robertson, C. E., Garza, I., 2015-09-30 06:50:45 AM
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Lambru, G., Shanahan, P., Matharu, M., 2015-09-30 06:50:45 AM
Background
The management of short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and with short-lasting unilateral neuralgiform headache attacks with autonomic symptoms (SUNA) remains challenging in view of the limited understanding of their pathophysiological mechanisms.
Methods
An initial observation that patients with both chronic migraine (CM) or cluster headache (CH) and SUNCT/SUNA receiving intravenous dihydroergotamine (IV DHE) had complained of dramatic worsening of the latter led to review of the case notes of patients with CM or CH and co-existent SUNCT/SUNA seen between 2008 and 2013 and who had a trial of IV DHE.
Results
Twenty-four patients were identified. IV DHE was ineffective for SUNCT/SUNA in 16 patients, while one patient reported a marginal improvement. Five patients reported dramatic worsening of the SUNCT/SUNA. Moreover, two patients developed new-onset SUNA during their first IV DHE infusion. Out of these seven patients, those requiring repeated courses of IV DHE consistently experienced exacerbations of SUNCT/SUNA which were suppressed with IV lidocaine.
Conclusions
DHE is an ineffective treatment option for SUNCT and SUNA. Physicians who intend to offer IV DHE to CH or CM patients should warn them that IV DHE could exacerbate and possibly even lead to a de novo onset of SUNCT/SUNA. In view of the reported worsening or new onset of SUNCT/SUNA in patients using dopamine agonists for the treatment of pituitary prolactinomas, we speculate that DHE might worsen or induce SUNCT and SUNA, at least in a sub-group of patients, through a perturbation in the dopaminergic system.
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Braunstein, D., Donnet, A., Pradel, V., Sciortino, V., Allaria-Lapierre, V., Lanteri-Minet, M., Micallef, J., 2015-09-30 06:50:45 AM
Introduction
The objective of this study was to estimate and to characterize the actual patterns of triptan use and overuse in France using a drug reimbursement database.
Methods
We included all people covered by the French General Health Insurance System (GHIS) from the Provence-Alpes-Côte-d'Azur (PACA) and Corsica administrative areas who had at least one dispensed dose of triptans between May 2010 and December 2011. All dispensed doses of triptans, migraine prophylactic treatment and psychotropic medications were extracted from the GHIS database. Triptan overuse was defined as triptan use >20 defined daily doses (DDD) per month on a regular basis for more than three consecutive months. Risk of overuse was assessed using logistic regression adjusted for gender and age.
Results
We included 99,540 patients who had at least one prescription of a triptan over the 20 months of the study. Among them, 2243 patients (2.3%) were identified as overusers and received 20.2% of the total DDD prescribed. Twelve percent of overusers and 6.9% of non-overusers were aged more than 65 years (OR: 1.81). Overusers did not have a greater number of prescribers and pharmacists than non-overusers. They were more frequently prescribed a prophylactic medication for migraine treatment (56.8% vs 35.9%, OR: 2.36), benzodiazepines (69.9% vs 54.7%, OR: 1.93) and antidepressants (49.4% vs 30.2%, OR: 2.33).
Conclusions
This work suggests that triptan overuse may be due to insufficient prescriber awareness of appropriate prescribing. The off-label prescription of triptans among the elderly necessitates investigating their cardiovascular risk profile in this sub-group.
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Esserlind, A.-L., Christensen, A. F., Steinberg, S., Grarup, N., Pedersen, O., Hansen, T., Werge, T., Hansen, T. F., Husemoen, L. L. N., Linneberg, A., Budtz-Jorgensen, E., Westergaard, M. L., Stefansson, H., Olesen, J., 2015-09-30 06:50:45 AM
Introduction
The objective of the study was to follow up and to test whether 12 previously identified migraine-associated single nucleotide polymorphisms were associated as risk factors and/or modifying factors for severe migraine traits in a Danish clinic-based population.
Methods
Semi-structured migraine interviews, blood sampling and genotyping were performed on 1806 unrelated migraineurs recruited from the Danish Headache Center. Genotyping was also performed on a control group of 6415 people with no history of migraine. Association analyses were carried out using logistic regression and odds ratios were calculated assuming an additive model for risk. The proxies for severe migraine traits (early onset of migraine; many lifetime attacks, prolonged migraine and tendency to chronification of migraine) were tested against the 12 single nucleotide polymorphisms and a combined genetic score in both a case-control and case-only logistic regression model.
Results
We successfully replicated five out of the 12 previously reported loci and confirmed the same direction of effects for all the 12 single nucleotide polymorphisms. In line with the recently published genome-wide association meta-analysis, the associations were significant for all migraine and migraine without aura but not for migraine with typical aura. Two single nucleotide polymorphisms (rs2274316 and rs11172113) conferred risk of many lifetime attacks inthe case-control analysis. In the case-only analysis, only three single nucleotide polymorphisms showed nominal association with many lifetime attacks and prolonged migraine attacks.
Conclusion
Our study supports previously reported findings on the association of several single nucleotide polymorphisms with migraine. It also suggests that the migraine susceptibility loci may be risk factors for severe migraine traits.
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Park, H.-E., Kim, J.-S., Park, J.-W., Lee, K.-S., 2015-09-30 06:50:45 AM
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Chhetri, S. K., Bindman, D., Joseph, J., Mathur, S., Shaunak, S., 2015-09-30 06:50:45 AM
There is little in the published neurological literature on acephalgic giant cell arteritis (GCA); even less commonly reported are the clinical, radiological and pathological features of GCA presenting with ischaemic stroke and stenosis/occlusion of the basal cerebral arteries. We report a fatal case of GCA manifesting as repeated episodes of cerebral ischaemia with radiological evidence of severe stenosis involving both internal carotid and vertebral arteries and post-mortem histopathological confirmation of GCA.
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Vodonos, A., Novack, V., Zlotnik, Y., Ifergane, G., 2015-09-30 06:50:45 AM
Background
Headache is a common condition, and a common complaint leading patients to emergency departments (ED). There have been a number of studies of the effect of environmental factors on headache, such as weather and air pollutants.
Methods
This retrospective cohort study included data on daily ED visits with a chief complaint of headache in Soroka University Medical Center (SUMC) during 2002–2012. Data on weather and air pollutants were obtained from monitor station in Be'er-Sheva. To estimate the short-term effects of air pollution and temperature on number of daily headache ED visits, we applied generalized linear mixed models (GLMM).
Results
A total of 22,021 ED visits were included in the analysis. An increase in 5℃ in temperature was associated with an increase in ED visits, relative risk (RR) = 1.042, (95% CI 1.009; 1.076). RR for headache was associated with an increase in 10 units of nitrogen dioxide (NO2), RR = 1.110 (95% CI 1.057; 1.167), with a higher effect for older patients.
Discussion
The current findings give evidence of an association between air pollution, weather and ED visits for headache, especially for NO2. Short-term increases in air pollution exposure may trigger headache by increasing pulmonary and systemic inflammation, increasing blood coagulability or altering endothelial function.
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Koehler, P. J., 2015-09-30 06:50:45 AM
Background
Christiaan Huygens (1629–1695) was a Dutch mathematician, physicist, and astronomer. He became well-known as inventor of the pendulum clock and described light as a wave phenomenon. He became Fellow of the Royal Society (London) and member of the Académie des Sciences (Paris). From the correspondence with family members and famous scientists, we learn that he suffered from frequent headaches.
Aim
To study Huygens' 22-volume Oeuvres Complètes (1888–1950) to find letters in which his headaches are mentioned and translate pertinent sections into English.
Conclusions
Although a posthumous diagnosis of Huygens' headaches is somewhat hazardous, the recurrent episodes with incapacitating headache and family history over two generations are suggestive for migraine. It becomes clear that it impeded his writing, reading, and research. From the letters we get an impression of the impact of the headache upon his life and the treatments that were applied in the 17th century.
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Qiu, C., Frederick, I. O., Sorensen, T., Aurora, S. K., Gelaye, B., Enquobahrie, D. A., Williams, M. A., 2015-09-30 06:50:45 AM
Background
Migraine is associated with sleep disturbances in men and non-pregnant women. However, relatively little is known about sleep disturbances among pregnant migraineurs. We investigated sleep disturbances among pregnant women with and without history of migraine.
Methods
This cross-sectional study was conducted among 1324 women who were recruited during early pregnancy. Migraine diagnoses were based on the International Classification of Headache Disorders-II criteria. The Pittsburgh Sleep Quality Index (PSQI) questionnaire was used to evaluate sleep-related characteristics including sleep duration, sleep quality, excessive daytime sleepiness, and other sleep traits. Multivariable logistic regression procedures were used to estimate adjusted odds ratios (AORs) and 95% confidence intervals (CIs).
Results
Migraineurs were more likely than non-migraineurs to report short sleep duration (<6.5 hours) (AOR = 1.47, 95% CI 1.07–2.02), poor sleep quality (PSQI>5) (AOR = 1.73, 95% CI 1.35–2.23), and daytime dysfunction due to sleepiness (AOR = 1.51, 95% CI 1.12–2.02). Migraineurs were also more likely than non-migraineurs to report taking sleep medication during pregnancy (AOR = 1.71, 95% CI 1.20–2.42). Associations were generally similar for migraine with or without aura. The odds of sleep disturbances were particularly elevated among pre-pregnancy overweight migraineurs.
Conclusion
Migraine headache and sleep disturbances are common comorbid conditions among pregnant women.
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de Vries, B., Anttila, V., Freilinger, T., Wessman, M., Kaunisto, M. A., Kallela, M., Artto, V., Vijfhuizen, L. S., Gobel, H., Dichgans, M., Kubisch, C., Ferrari, M. D., Palotie, A., Terwindt, G. M., van den Maagdenberg, A. M., on behalf of the International Headache Genetics Consortium, 2015-09-30 06:50:45 AM
Background
Before the genome-wide association (GWA) era, many hypothesis-driven candidate gene association studies were performed that tested whether DNA variants in genes that had been selected based on prior knowledge about migraine pathophysiology were associated with migraine. Most studies involved small sample sets without robust replication, thereby making the risk of false-positive findings high. Genome-wide marker data of thousands of migraine patients and controls from the International Headache Genetics Consortium provide a unique opportunity to re-evaluate key findings from candidate gene association studies (and other non-GWA genetic studies) in a much larger data set.
Methods
We selected 21 genes from published candidate gene association studies and six additional genes from other non-GWA genetic studies in migraine. Single nucleotide polymorphisms (SNPs) in these genes, as well as in the regions 500 kb up- and downstream, were inspected in IHGC GWAS data from 5175 clinic-based migraine patients with and without aura and 13,972 controls.
Results
None of the SNPs in or near the 27 genes, including the SNPs that were previously found to be associated with migraine, reached the Bonferroni-corrected significance threshold; neither when analyzing all migraine patients together, nor when analyzing the migraine with and without aura patients or males and females separately.
Conclusion
The available migraine GWAS data provide no clear evidence for involvement of the previously reported most promising candidate genes in migraine.
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Maarbjerg, S., Wolfram, F., Gozalov, A., Olesen, J., Bendtsen, L., 2015-09-30 06:50:45 AM
Background
Previous studies demonstrated that a severe neurovascular contact (NVC) causing displacement or atrophy of the trigeminal nerve is highly associated with classical trigeminal neuralgia (TN). There are no studies describing the association between the clinical characteristics of TN and severe NVC.
Methods
Clinical characteristics were prospectively collected from consecutive TN patients using semi-structured interviews in a cross-sectional study design. We evaluated 3.0 Tesla MRI blinded to the symptomatic side.
Results
We included 135 TN patients. Severe NVC was more prevalent in men (75%) compared to women (38%) (p < 0.001), and the odds in favor of severe NVC on the symptomatic side were 5.1 times higher in men compared to women (95% CI 2.3–10.9, p < 0.001). There was no difference between patients with and without severe NVC in age (≥60 years vs. <60) (OR 1.6 95% CI (0.8–3.4), p = 0.199) or duration of disease (p = 0.101).
Conclusions
Severe NVC was much more prevalent in men than in women, who may more often have other disease etiologies causing or contributing to TN. Severe NVC was not associated with age or with duration of disease.
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Greco, R., Bandiera, T., Mangione, A., Demartini, C., Siani, F., Nappi, G., Sandrini, G., Guijarro, A., Armirotti, A., Piomelli, D., Tassorelli, C., 2015-09-30 06:50:45 AM
Background
Systemic nitroglycerin (NTG) activates brain nuclei involved in nociceptive transmission as well as in neuroendocrine and autonomic functions in rats. These changes are considered relevant for migraine because NTG consistently provokes spontaneous-like migraine attacks in migraineurs. Several studies have suggested a relationship between the endocannabinoid levels and pain mediation in migraine. URB937, a peripheral inhibitor of fatty acid amide hydrolase (FAAH)—the enzyme that degrades anandamide, produces analgesia in animal models of pain, but there is no information on its effects in migraine.
Aim
We evaluated whether URB937 alters nociceptive responses in the animal model of migraine based on NTG administration in male rats, using the tail flick test and the plantar and orofacial formalin tests, under baseline conditions and after NTG administration. Furthermore, we investigated whether URB937 affects NTG-induced c-Fos expression in the brain.
Results
During the tail flick test, URB937 showed an antinociceptive effect in baseline conditions and it blocked NTG-induced hyperalgesia. URB937 also proved effective in counteracting NTG-induced hyperalgesia during both the plantar and orofacial formalin tests. Mapping of brain nuclei activated by NTG indicates that URB937 significantly reduces c-Fos expression in the nucleus trigeminalis caudalis and the locus coeruleus.
Conclusions
The data suggest that URB937 is capable of changing, probably via indirect mechanisms, the functional status of central structures that are important for pain transmission in an animal model of migraine.
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Munoz-Islas, E., Gonzalez-Hernandez, A., Lozano-Cuenca, J., Ramirez-Rosas, M. B., Medina-Santillan, R., Centurion, D., MaassenVanDenBrink, A., Villalon, C. M., 2015-09-30 06:50:45 AM
Background
During migraine, capsaicin-sensitive trigeminal sensory nerves release calcitonin gene-related peptide (CGRP), resulting in cranial vasodilatation and central nociception. Moreover, 5-HT is involved in the pathophysiology of migraine and depression. Interestingly, some limited lines of evidence suggest that fluoxetine may be effective in migraine prophylaxis, but the underlying mechanisms are uncertain. Hence, this study investigated the canine external carotid vasodilator responses to capsaicin, α-CGRP and acetylcholine before and after acute and chronic oral treatment with fluoxetine.
Methods
Forty-eight vagosympathectomised male mongrel dogs were prepared to measure blood pressure, heart rate and external carotid blood flow. The thyroid artery was cannulated for infusions of agonists. In 16 of these dogs, a spinal cannula was inserted (C1–C3) for infusions of 5-HT.
Results
The external carotid vasodilator responses to capsaicin, α-CGRP and acetylcholine remained unaffected after intracarotid or i.v. fluoxetine. In contrast, the vasodilator responses to capsaicin, but not those to α-CGRP or acetylcholine, were inhibited after chronic oral treatment with fluoxetine (300 µg/kg; for 90 days) or intrathecal 5-HT.
Conclusions
Chronic oral fluoxetine inhibited capsaicin-induced external carotid vasodilatation, and this inhibition could partly explain its potential prophylactic antimigraine action.
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Wei, X., Yan, J., Tillu, D., Asiedu, M., Weinstein, N., Melemedjian, O., Price, T., Dussor, G., 2015-09-30 06:50:45 AM
Background
Stress is commonly reported to contribute to migraine although mechanisms by which this may occur are not fully known. The purpose of these studies was to examine whether norepinephrine (NE), the primary sympathetic efferent transmitter, acts on processes in the meninges that may contribute to the pain of migraine.
Methods
NE was applied to rat dura using a behavioral model of headache. Primary cultures of rat trigeminal ganglia retrogradely labeled from the dura mater and of rat dural fibroblasts were prepared. Patch-clamp electrophysiology, Western blot, and ELISA were performed to examine the effects of NE. Conditioned media from NE-treated fibroblast cultures was applied to the dura using the behavioral headache model.
Results
Dural injection both of NE and media from NE-stimulated fibroblasts caused cutaneous facial and hindpaw allodynia in awake rats. NE application to cultured dural afferents increased action potential firing in response to current injections. Application of NE to dural fibroblasts increased phosphorylation of ERK and caused the release of interleukin-6 (IL-6).
Conclusions
These data demonstrate that NE can contribute to pro-nociceptive signaling from the meninges via actions on dural afferents and dural fibroblasts. Together, these actions of NE may contribute to the headache phase of migraine.
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Planche, V., Dousset, V., Ouallet, J. C., Tourdias, T., 2015-09-30 06:50:45 AM
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Olesen, J., Ashina, M., 2015-09-30 06:50:45 AM
Introduction
For many years, scientists have debated the possibility that an individual "migraine threshold" determines the likelihood with which individuals may express migraine attacks.
Discussion
Recent discoveries provided evidence for both genetic and environmental influences on individual migraine expression. The question is whether any person may express a migraine attack given a sufficiently strong stimulus or provocation. Here, we reviewed and discussed the ability of nitric oxide to induce migraine-like attacks in normal individuals.
Conclusion
Experimental data show that normal individuals may develop a migraine-like attack and that the human data point to different ways of further developing existing animal and human models.
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Annals of Biomedical Engineering
A Pressure Plate-Based Method for the Automatic Assessment of Foot Strike Patterns During Running
Abstract
The foot strike pattern (FSP, description of how the foot touches the ground at impact) is recognized to be a predictor of both performance and injury risk. The objective of the current investigation was to validate an original foot strike pattern assessment technique based on the numerical analysis of foot pressure distribution. We analyzed the strike patterns during running of 145 healthy men and women (85 male, 60 female). The participants ran on a treadmill with integrated pressure plate at three different speeds: preferred (shod and barefoot 2.8 ± 0.4 m/s), faster (shod 3.5 ± 0.6 m/s) and slower (shod 2.3 ± 0.3 m/s). A custom-designed algorithm allowed the automatic footprint recognition and FSP evaluation. Incomplete footprints were simultaneously identified and corrected from the software itself. The widely used technique of analyzing high-speed video recordings was checked for its reliability and has been used to validate the numerical technique. The automatic numerical approach showed a good conformity with the reference video-based technique (ICC = 0.93, p < 0.01). The great improvement in data throughput and the increased completeness of results allow the use of this software as a powerful feedback tool in a simple experimental setup.
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Seeing Through the Surface: Non-invasive Characterization of Biomaterial–Tissue Interactions Using Photoacoustic Microscopy
Abstract
At the intersection of life sciences, materials science, engineering, and medicine, regenerative medicine stands out as a rapidly progressing field that aims at retaining, restoring, or augmenting tissue/organ functions to promote the human welfare. While the field has witnessed tremendous advancements over the past few decades, it still faces many challenges. For example, it has been difficult to visualize, monitor, and assess the functions of the engineered tissue/organ constructs, particularly when three-dimensional scaffolds are involved. Conventional approaches based on histology are invasive and therefore only convey end-point assays. The development of volumetric imaging techniques such as confocal and ultrasonic imaging has enabled direct observation of intact constructs without the need of sectioning. However, the capability of these techniques is often limited in terms of penetration depth and contrast. In comparison, the recently developed photoacoustic microscopy (PAM) has allowed us to address these issues by integrating optical and ultrasonic imaging to greatly reduce the effect of tissue scattering of photons with one-way ultrasound detection while retaining the high optical absorption contrast. PAM has been successfully applied to a number of studies, such as observation of cell distribution, monitoring of vascularization, and interrogation of biomaterial degradation. In this review article, we highlight recent progress in non-invasive and volumetric characterization of biomaterial–tissue interactions using PAM. We also discuss challenges ahead and envision future directions.
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Haemodynamics and Flow Modification Stents for Peripheral Arterial Disease: A Review
Abstract
Endovascular stents are widely used for the treatment of peripheral arterial disease (PAD). However, the development of in-stent restenosis and downstream PAD progression remain a challenge. Stent revascularisation of PAD causes arterial trauma and introduces abnormal haemodynamics, which initiate complicated biological processes detrimental to the arterial wall. The interaction between stent struts and arterial cells in contact, and the blood flow field created in a stented region, are highly affected by stent design. Spiral flow is known as a normal physiologic characteristic of arterial circulation and is believed to prevent the development of flow disturbances. This secondary flow motion is lost in atheromatous disease and its re-introduction after endovascular treatment of PAD has been suggested as a method to induce stabilised and coherent haemodynamics. Stent designs able to generate spiral flow may support endothelial function and therefore increase patency rates. This review is focused on secondary flow phenomena in arteries and the development of flow modification stent technologies for the treatment of PAD.
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30 Years of Neurosurgical Robots: Review and Trends for Manipulators and Associated Navigational Systems
Abstract
This review provides an examination of contemporary neurosurgical robots and the developments that led to them. Improvements in localization, microsurgery and minimally invasive surgery have made robotic neurosurgery viable, as seen by the success of platforms such as the CyberKnife and neuromate. Neurosurgical robots can now perform specific surgical tasks such as skull-base drilling and craniotomies, as well as pedicle screw and cochlear electrode insertions. Growth trends in neurosurgical robotics are likely to continue but may be tempered by concerns over recent surgical robot recalls, commercially-driven surgeon training, and studies that show operational costs for surgical robotic procedures are often higher than traditional surgical methods. We point out that addressing performance issues related to navigation-related registration is an active area of research and will aid in improving overall robot neurosurgery performance and associated costs.
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Structural Mechanics Predictions Relating to Clinical Coronary Stent Fracture in a 5 Year Period in FDA MAUDE Database
Abstract
Endovascular stents are the mainstay of interventional cardiovascular medicine. Technological advances have reduced biological and clinical complications but not mechanical failure. Stent strut fracture is increasingly recognized as of paramount clinical importance. Though consensus reigns that fractures can result from material fatigue, how fracture is induced and the mechanisms underlying its clinical sequelae remain ill-defined. In this study, strut fractures were identified in the prospectively maintained Food and Drug Administration's (FDA) Manufacturer and User Facility Device Experience Database (MAUDE), covering years 2006–2011, and differentiated based on specific coronary artery implantation site and device configuration. These data, and knowledge of the extent of dynamic arterial deformations obtained from patient CT images and published data, were used to define boundary conditions for 3D finite element models incorporating multimodal, multi-cycle deformation. The structural response for a range of stent designs and configurations was predicted by computational models and included estimation of maximum principal, minimum principal and equivalent plastic strains. Fatigue assessment was performed with Goodman diagrams and safe/unsafe regions defined for different stent designs. Von Mises stress and maximum principal strain increased with multimodal, fully reversed deformation. Spatial maps of unsafe locations corresponded to the identified locations of fracture in different coronary arteries in the clinical database. These findings, for the first time, provide insight into a potential link between patient adverse events and computational modeling of stent deformation. Understanding of the mechanical forces imposed under different implantation conditions may assist in rational design and optimal placement of these devices.
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Comparing Postural Stability Entropy Analyses to Differentiate Fallers and Non-fallers
Abstract
The health and financial cost of falls has spurred research to differentiate the characteristics of fallers and non-fallers. Postural stability has received much of the attention with recent studies exploring various measures of entropy. This study compared the discriminatory ability of several entropy methods at differentiating two paradigms in the center-of-pressure of elderly individuals: (1) eyes open (EO) vs. eyes closed (EC) and (2) fallers (F) vs. non-fallers (NF). Methods were compared using the area under the curve (AUC) of the receiver-operating characteristic curves developed from logistic regression models. Overall, multiscale entropy (MSE) and composite multiscale entropy (CompMSE) performed the best with AUCs of 0.71 for EO/EC and 0.77 for F/NF. When methods were combined together to maximize the AUC, the entropy classifier had an AUC of for 0.91 the F/NF comparison. These results suggest researchers and clinicians attempting to create clinical tests to identify fallers should consider a combination of every entropy method when creating a classifying test. Additionally, MSE and CompMSE classifiers using polar coordinate data outperformed rectangular coordinate data, encouraging more research into the most appropriate time series for postural stability entropy analysis.
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Biomechanical Challenges to Polymeric Biodegradable Stents
Abstract
Biodegradable implants have demonstrated clinical success in simple applications (e.g., absorbable sutures) and have shown great potential in many other areas of interventional medicine, such as localized drug delivery, engineered tissue scaffolding, and structural implants. For endovascular stenting and musculoskeletal applications, they can serve as temporary mechanical support that provides a smooth stress-transfer from the degradable implant to the healing tissue. However, for more complex device geometries, in vivo environments, and evolving load-bearing functions, such as required for vascular stents, there are considerable challenges associated with the use of biodegradable materials. A biodegradable stent must restore blood flow and provide support for a predictable appropriate period to facilitate artery healing, and subsequently, fail safely and be absorbed in a controllable manner. Biodegradable polymers are typically weaker than metals currently employed to construct stents, so it is difficult to ensure sufficient strength to keep the artery open and alleviate symptoms acutely while keeping other design parameters within clinically acceptable ranges. These design challenges are serious, given the general lack of understanding of biodegradable polymer behavior and evolution in intimal operating conditions. The modus operandi is mainly empirical and relies heavily on trial-and-error methodologies burdened by difficult, resource-expensive, and time-consuming experiments. We are striving for theoretical advancements systematizing the empirical knowledge into rational frameworks that could be cast into in silico tools for simulation and product development optimization. These challenges are evident when one considers that there are no biodegradable stents on the US market despite more than 30 years of development efforts (and currently only a couple with CE mark). This review summarizes previous efforts at implementing biodegradable stents, discusses the specific challenges involved, and presents recently developed material-modeling frameworks that can benefit this exciting field.
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An eFace-Template Method for Efficiently Generating Patient-Specific Anatomically-Detailed Facial Soft Tissue FE Models for Craniomaxillofacial Surgery Simulation
Abstract
Accurate surgical planning and prediction of craniomaxillofacial surgery outcome requires simulation of soft-tissue changes following osteotomy. This can only be accomplished on an anatomically-detailed facial soft tissue model. However, current anatomically-detailed facial soft tissue model generation is not appropriate for clinical applications due to the time intensive nature of manual segmentation and volumetric mesh generation. This paper presents a novel semi-automatic approach, named eFace-template method, for efficiently and accurately generating a patient-specific facial soft tissue model. Our novel approach is based on the volumetric deformation of an anatomically-detailed template to be fitted to the shape of each individual patient. The adaptation of the template is achieved by using a hybrid landmark-based morphing and dense surface fitting approach followed by a thin-plate spline interpolation. This methodology was validated using 4 visible human datasets (regarded as gold standards) and 30 patient models. The results indicated that our approach can accurately preserve the internal anatomical correspondence (i.e., muscles) for finite element modeling. Additionally, our hybrid approach was able to achieve an optimal balance among the patient shape fitting accuracy, anatomical correspondence and mesh quality. Furthermore, the statistical analysis showed that our hybrid approach was superior to two previously published methods: mesh-matching and landmark-based transformation. Ultimately, our eFace-template method can be directly and effectively used clinically to simulate the facial soft tissue changes in the clinical application.
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Automatic Sleep Stage Scoring Using Time-Frequency Analysis and Stacked Sparse Autoencoders
Abstract
We developed a machine learning methodology for automatic sleep stage scoring. Our time-frequency analysis-based feature extraction is fine-tuned to capture sleep stage-specific signal features as described in the American Academy of Sleep Medicine manual that the human experts follow. We used ensemble learning with an ensemble of stacked sparse autoencoders for classifying the sleep stages. We used class-balanced random sampling across sleep stages for each model in the ensemble to avoid skewed performance in favor of the most represented sleep stages, and addressed the problem of misclassification errors due to class imbalance while significantly improving worst-stage classification. We used an openly available dataset from 20 healthy young adults for evaluation. We used a single channel of EEG from this dataset, which makes our method a suitable candidate for longitudinal monitoring using wearable EEG in real-world settings. Our method has both high overall accuracy (78%, range 75–80%), and high mean \(F_1\) -score (84%, range 82–86%) and mean accuracy across individual sleep stages (86%, range 84–88%) over all subjects. The performance of our method appears to be uncorrelated with the sleep efficiency and percentage of transitional epochs in each recording.
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Integrated Stent Models Based on Dimension Reduction: Review and Future Perspectives
Abstract
Stent modeling represents a challenging task from both the theoretical and numerical viewpoints, due to its multi-physics nature and to the complex geometrical configuration of these devices. In this light, dimensional model reduction enables a comprehensive geometrical and physical description of stenting at affordable computational costs. In this work, we aim at reviewing dimensional model reduction of stent mechanics and drug release. Firstly, we address model reduction techniques for the description of stent mechanics, aiming to illustrate how a three-dimensional stent model can be transformed into a collection of interconnected one-dimensional rods, called a "stent net". Secondly, we review available model reduction methods similarly applied to drug release, in which the "stent net" concept is adopted for modeling of drug elution. As a result, drug eluting stents are described as a distribution of concentrated drug release sources located on a graph that fully represents the stent geometry. Lastly, new results about the extension of these model reduction approaches to biodegradable stents are also discussed.
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