Genome-wide association study of sporadic brain arteriovenous malformations.

BACKGROUND: The pathogenesis of sporadic brain arteriovenous malformations (BAVMs) remains unknown, but studies suggest a genetic component. We estimated the heritability of sporadic BAVM and performed a genome-wide association study (GWAS) to investigate association of common single nucleotide polymorphisms (SNPs) with risk of sporadic BAVM in the international, multicentre Genetics of Arteriovenous Malformation (GEN-AVM) consortium. METHODS: The Caucasian discovery cohort included 515 BAVM cases and 1191 controls genotyped using Affymetrix genome-wide SNP arrays. Genotype data were imputed to 1000 Genomes Project data, and well-imputed SNPs (>0.01 minor allele frequency) were analysed for association with BAVM. 57 top BAVM-associated SNPs (51 SNPs with p<10(-05) or p<10(-04) in candidate pathway genes, and 6 candidate BAVM SNPs) were tested in a replication cohort including 608 BAVM cases and 744 controls. RESULTS: The estimated heritability of BAVM was 17.6% (SE 8.9%, age and sex-adjusted p=0.015). None of the SNPs were significantly associated with BAVM in the replication cohort after correction for multiple testing. 6 SNPs had a nominal p<0.1 in the replication cohort and map to introns in EGFEM1P, SP4 and CDKAL1 or near JAG1 and BNC2. Of the 6 candidate SNPs, 2 in ACVRL1 and MMP3 had a nominal p<0.05 in the replication cohort. CONCLUSIONS: We performed the first GWAS of sporadic BAVM in the largest BAVM cohort assembled to date. No GWAS SNPs were replicated, suggesting that common SNPs do not contribute strongly to BAVM susceptibility. However, heritability estimates suggest a modest but significant genetic contribution.

Surgical management of intracranial subependymomas.

BACKGROUND: Intracranial subependymomas are rare, slow-growing and usually non-invasive tumors. The aim of this study was to analyze our experience with the surgical treatment of intracranial subependymomas. METHODS: Between 1991 and 2007, 11 patients with intracranial subependymomas had surgery in our institution. Mean age of the patients was 54.4 years (ranging from 40 to 85 years). RESULTS: Tumors were located in the fourth ventricle in seven patients and in the lateral ventricle in four patients. Most patients presented with symptoms related to intracranial hypertension and/or cerebellar signs and symptoms (headache: eight patients; dizziness: six patients; nausea: six patients; gait ataxia: four patients), one patient with cognitive decline and flattened affect, and one patient with a hemiparesis. Six patients presented with hydrocephalus, but only one needed a permanent cerebrospinal fluid (CSF) shunt. Complete removal of the tumor was possible in eight cases. Following surgery, only one patient experienced a permanent drop of his Karnofsky Performance Index (from 70 to 60). Median follow-up was 37 months. There were no true recurrences during follow-up. A second surgery was required 7 years after the first operation for progression of an incompletely resected tumor. CONCLUSIONS: Removal of symptomatic subependymomas can be performed safely. Prognosis is excellent after a complete resection. The potential for a surgical cure, low surgical complication rates and the risk of undertreatment of a more aggressive tumor together may justify surgery for asymptomatic lesions.

Number of metastases, serum lactate dehydrogenase level, and type of treatment are prognostic factors in patients with brain metastases of malignant melanoma.

BACKGROUND: This multicenter study aimed to identify prognostic factors in patients with brain metastases from malignant melanoma (BM-MM). METHODS: In a retrospective survey in 9 cancer centers of the German Cancer Society, 692 patients were identified with BM-MM during the period 1986 through 2007. Overall survival was analyzed using a Kaplan-Meier estimator and compared with log-rank analysis. Cox proportional hazards models were used to identify prognostic factors significant for survival. RESULTS: The median overall survival of the entire cohort was 5.0 months (95% confidence interval [95% CI], 4 months-5 months). Significant prognostic factors in the univariate Kaplan-Meier analysis were Karnofsky performance status (≥70% vs <70%; P < .001), number of BM-MM (single vs multiple; P < .001), pretreatment levels of lactate dehydrogenase (LDH) (normal vs elevated; P < .001) and S-100 (normal vs elevated; P < .001), prognostic groups according to Radiation Therapy Oncology Group (class I vs class II vs class III; P = .0485), and treatment choice (for the cohort with single BM-MM only) (stereotactic radiotherapy or neurosurgical metastasectomy vs others; P = .036). Cox proportional hazards models revealed pretreatment elevated level of serum LDH (hazard ratio [HR], 1.6; 95% CI, 1.3-2.0 [P = .00013]) and number of BM-MM (HR, 1.6; 95% CI, 1.3-2.0 [P = .00011]) to be independent prognostic variables in the entire cohort, whereas in patients with a single BM-MM, treatment choice (HR, 1.5; 95% CI, 1.1-1.9 [P = .0061]) was identified as a unique prognostic factor. CONCLUSIONS: The overall survival of patients with BM-MM primarily depends on the number of metastases and pretreatment level of LDH. In the case of a single brain metastasis, stereotactic radiotherapy or neurosurgical metastasectomy is by far the most important factor for improving survival.

Spinal epidural arteriovenous fistula with perimedullary drainage. Case report and pathomechanical considerations.

The classic angiographically demonstrated features of spinal dural arteriovenous fistulas are shunts of radiculomeningeal branches with radicular veins draining exclusively in the direction of perimedullary veins and thereby causing venous congestion. These shunts are located at the point where the radicular vein passes the dura mater. Spinal epidural arteriovenous shunts, however, normally do not drain into the perimedullary veins and are, therefore, asymptomatic, presumably because of a postulated reflux-impeding mechanism between the dural sleeves. The authors report on a patient in whom an epidural arteriovenous shunt showed delayed retrograde drainage into perimedullary veins, leading to the classic clinical (and magnetic resonance imaging-based) findings of venous congestion. Intraoperatively the angiographically established diagnosis was confirmed. Coagulation of both the epidural shunt zone and the radicular vein resulted in complete obliteration of the fistula, as confirmed on repeated angiography. This rare type of fistula should stimulate considerations on the role of valvelike mechanisms normally impeding retrograde flow from the epidural plexus to perimedullary veins and suggest that, in certain pathological circumstances, epidural fistulas can drain retrogradely into perimedullary veins as an infrequent variant of spinal arteriovenous shunts.