Karsten Wrede

Molecular Classification of Low-Grade Diffuse Gliomas

The current World Health Organization classification recognizes three histological types of grade II low-grade diffuse glioma (diffuse astrocytoma, oligoastrocytoma, and oligodendroglioma). However, the diagnostic criteria, in particular for oligoastrocytoma, are highly subjective. The aim of our study was to establish genetic profiles for diffuse gliomas and to estimate their predictive impact. In this study, we screened 360 World Health Organization grade II gliomas for mutations in the IDH1, IDH2, and TP53 genes and for 1p/19q loss and correlated these with clinical outcome. Most tumors (86%) were characterized genetically by TP53 mutation plus IDH1/2 mutation (32%), 1p/19q loss plus IDH1/2 mutation (37%), or IDH1/2 mutation only (17%). TP53 mutations only or 1p/19q loss only was rare (2 and 3%, respectively). The median survival of patients with TP53 mutation ± IDH1/2 mutation was significantly shorter than that of patients with 1p/19q loss ± IDH1/2 mutation (51.8 months vs. 58.7 months, respectively; P = 0.0037). Multivariate analysis with adjustment for age and treatment confirmed these results (P = 0.0087) and also revealed that TP53 mutation is a significant prognostic marker for shorter survival (P = 0.0005) and 1p/19q loss for longer survival (P = 0.0002), while IDH1/2 mutations are not prognostic (P = 0.8737). The molecular classification on the basis of IDH1/2 mutation, TP53 mutation, and 1p/19q loss has power similar to histological classification and avoids the ambiguity inherent to the diagnosis of oligoastrocytoma.

Direct posterior reduction and fixation for the treatment of basilar invagination with atlantoaxial dislocation.

OBJECTIVETo report the surgical technique and clinical results for the treatment of basilar invagination (BI) with atlantoaxial dislocation (AAD) by direct posterior reduction and fixation using intraoperative distraction between the occiput and C2 pedicle screws. METHODSFrom May 2004 to June 2008, 29 patients who had BI with AAD were surgically treated in our department. Pre- and postoperative dynamic cervical x-rays, computed tomographic scans, and 3-dimensional reconstruction views were performed to assess the degree of dislocation. Ventral compression of the cervicomedullary junction was evaluated by magnetic resonance imaging. For all patients, reduction of the AAD was conducted by intraoperative distraction between the occiput and C2 pedicle screws using a direct posterior approach. RESULTSFollow-up ranged from 6 to 50 months in 28 patients. Clinical symptoms improved in 26 patients (92.9%) and were stable in 2 patients (7.1%) without postoperative deterioration. Radiologically, complete or more than 50% reduction was achieved in 27 of 28 patients (96.4%). In 1 patient, the reduction was less than 50% because the direction of the facets on 1 side of the C1–C2 joint was vertically oriented, instead of horizontal. Overall, good decompression and bone fusion were shown on postoperative magnetic resonance imaging, computed tomography, or x-ray scans for all patients. There was 1 death in the series because of basilar artery thrombosis 1 week after the operation. CONCLUSIONThe direct posterior distraction technique between occiput and C2 pedicle screws is an effective, simple, fast, and safe method for the treatment of BI with AAD. Transoral odontoidectomy and cervical traction for the treatment of BI with AAD should be reconsidered.

Alterations in the RB1 pathway in low-grade diffuse gliomas lacking common genetic alterations.

We recently reported that the vast majority (>90%) of low‐grade diffuse gliomas (diffuse astrocytoma, oligoastrocytoma and oligodendroglioma) carry at least one of the following genetic alterations: IDH1/2 mutation, TP53 mutation or 1p/19q loss. Only 7% of cases were triple‐negative (ie, lacking any of these alterations). In the present study, array comparative genomic hybridization (CGH) in 15 triple‐negative WHO grade II gliomas (eight diffuse astrocytomas and seven oligodendrogliomas) showed loss at 9p21 (p14ARF, p15INK4b, p16INK4a loci) and 13q14–13q32 (containing the RB1 locus) in three and two cases, respectively. Further analyses in 31 triple‐negative cases as well as a total of 160 non‐triple‐negative cases revealed that alterations in the RB1 pathway (homozygous deletion and promoter methylation of the p15INK4b, p16INK4a and RB1 genes) were significantly more frequent in triple‐negative (26%) than in non‐triple‐negative cases (11%; P = 0.0371). Multivariate analysis after adjustment for age, histology and treatment showed that RB1 pathway alterations were significantly associated with unfavorable outcome for patients with low‐grade diffuse glioma [hazard ratio, 3.024 (1.279–6.631); P = 0.0057]. These results suggest that a fraction of low‐grade diffuse gliomas lacking common genetic alterations may develop through a distinct genetic pathway, which may include loss of cell‐cycle control regulated by the RB1 pathway.

Time-of-flight magnetic resonance angiography at 7 T using venous saturation pulses with reduced flip angles.

ObjectivesThe visibility of the vasculature in time-of-flight (TOF) magnetic resonance angiography (MRA) highly profits from increased magnetic field strengths. However, the application of additional saturation pulses for suppression of the venous system is often not possible at 7 T; to remain within the regulatory specific absorption rate (SAR) limits, the repetition time (TR) needs to be prolonged, preventing the acquisition of high-resolution MRA data sets within clinically acceptable acquisition times. In this work, saturation pulses were modified regarding flip angle and duration to meet SAR constraints and minimize total measurement time. Materials and MethodsTo ameliorate SAR restrictions, the variable-rate selective excitation (VERSE) algorithm was used for both excitation and saturation radio frequency pulses. In this way, saturation pulses (executed every TR) become applicable in high-resolution TOF MRA protocols but still lengthen total measurement time notably. In this work, saturation pulses were further modified in terms of flip angle and duration to meet SAR constraints and minimize total measurement time. ResultsIn the considered parameter range for excitation flip angle &agr; of 15° to 35° and TR of 20 ms to 35 ms, sufficient saturation flip angles (&agr;SAT) were 30° to 50°. ConclusionsThis work shows that by lowering the flip angle &agr;SAT, saturation pulses can be applied in high-resolution clinical TOF protocols using a TR as short as 20 ms. An &agr;SAT of &agr; + 15° is sufficient for suppression of the venous system in TOF MRA protocols in the parameter range normally used at 7 T. Instead of the standard 90° saturation pulse, only half the flip angle (or even less) is necessary, substantially ameliorating SAR constraints and enabling acquisition of high resolution in acceptable imaging time.

Frequent BRAF Gain in Low‐Grade Diffuse Gliomas with 1p/19q Loss

Chromosomal 7q34 duplication and BRAF‐KIAA1549 fusion is a characteristic genetic alteration in pilocytic astrocytomas. 7q34 gain appears to be common in diffuse astrocytomas, but its significance is unclear. We assessed BRAF gain and BRAF mutations in 123 low‐grade diffuse gliomas, including 55 diffuse astrocytomas, 18 oligoastrocytomas and 50 oligodendrogliomas. Quantitative polymerase chain reaction (PCR) revealed BRAF gain in 17/50 (34%) oligodendrogliomas, a significantly higher frequency than in diffuse astrocytomas (7/55; 13%; P = 0.0112). BRAF gain was common in low‐grade diffuse gliomas with 1p/19q loss (39%) and those lacking any of the genetic alterations analyzed (31%), but was rare in those with TP53 mutations (2%). Logistic regression analysis showed a significant positive association between 1p/19q loss and BRAF gain (P = 0.0032) and a significant negative association between TP53 mutations and BRAF gain (P = 0.0042). Fluorescence in situ hybridization (FISH) analysis of 26 low‐grade diffuse gliomas with BRAF gain additionally revealed BRAF‐KIAA1549 fusion in one oligodendroglioma. Sequencing of cDNA in 17 low‐grade diffuse gliomas showed BRAF‐KIAA1549 fusion in another oligodendroglioma. A BRAFV600E mutation was also detected in one oligodendroglioma, and a BRAFA598V in one diffuse astrocytoma. These results suggest that low‐grade diffuse gliomas with 1p/19q loss have frequent BRAF gains, and a small fraction of oligodendrogliomas may show BRAF‐KIAA1549 fusion.

Alterations in functional connectivity of resting state networks during experimental endotoxemia - An exploratory study in healthy men.

Systemic inflammation impairs mood and cognitive functions, and seems to be involved in the pathophysiology of psychiatric disorders. Functional magnetic resonance imaging (fMRI) studies revealed altered task-related blood-oxygen-level-dependent (BOLD) responses during experimental endotoxemia, but little is known about effects of systemic inflammation on resting-state activity of the brain. Thus, we conducted a randomized, placebo-controlled study in healthy men receiving an intravenous injection of either low-dose (0.4 ng/kg) lipopolysaccharide (LPS) (N=20) or placebo (N=25). Resting state activity was measured at baseline and 3.5h post-injection. Based on a two (condition) × two (group) design, we used multi-subject independent component analysis (ICA) to decompose and estimate functional connectivity within resting-state networks (RSNs). Seed-based analyses were applied to investigate the effect of LPS on the functional coupling for a priori-defined regions-of-interest (ROIs). ICA analyses identified 13 out of 35 components displaying common RSNs. Seed based analysis revealed greater functional connectivity between the left thalamus and the cerebellum after LPS compared to placebo administration, while the functional coupling between seeds within the amygdala, insula, and cingulate cortex and various brain regions including parieto-frontal networks was significantly reduced. Within the LPS group, endotoxin-induced increases in Interleukin (IL)-6 were significantly associated with resting-state connectivity between the left thalamus and left precuneus as well as the right posterior cingulate cortex. In summary, this exploratory study provides first evidence that systemic inflammation affects the coupling and regulation of multiple networks within the human brain at rest.

The CHESS score: a simple tool for early prediction of shunt dependency after aneurysmal subarachnoid hemorrhage

Acute hydrocephalus is an early and common complication of aneurysmal subarachnoid hemorrhage (SAH). However, considerably fewer patients develop chronic hydrocephalus requiring shunt placement. Our aim was to develop a risk score for early identification of patients with shunt dependency after SAH.

7 Tesla MPRAGE imaging of the intracranial arterial vasculature: nonenhanced versus contrast-enhanced.

PURPOSE To intraindividually compare the delineation of intracranial arterial vasculature in nonenhanced versus contrast-enhanced magnetization prepared rapid gradient echo (MPRAGE) imaging at 7 Tesla (T). MATERIALS AND METHODS Sixteen subjects were examined on a 7 T whole-body magnetic resonance system (Magnetom 7T) equipped with a 32-channel transmit/receive head coil. MPRAGE imaging was performed pre- and postcontrast after the application of 0.1 mmol/kg bodyweight gadobutrol. For qualitative analysis, the delineation of the intracranial arteries, overall image quality, and image impairment were assessed in the nonenhanced and contrast-enhanced datasets using a 5-point scale (5 = excellent to 1 = nondiagnostic). Additionally, contrast ratios (CR) of the middle cerebral artery in correlation to surrounding gray matter in nonenhanced and postcontrast images were obtained. For statistical analysis a Wilcoxon signed-rank test was applied. RESULTS Nonenhanced MPRAGE imaging offered an excellent delineation of the central vessel segments of the anterior circulation (mean anterior circulation 4.6) and a moderate- to high-quality assessment of the vessels of the posterior circulation (mean posterior circulation 3.9). Vessel delineation was improved in all assessed segments in the contrast-enhanced datasets, except for the cavernous segment of the internal carotid artery. Quantitative analysis revealed a mild, nonsignificant increase in CR mean values of the M1 segment (CRnonenhanced 0.67; CRcontrast-enhanced 0.69). CONCLUSION Our results demonstrate the high diagnostic value of nonenhanced 7 T MPRAGE imaging for the assessment of the intracranial arterial vasculature, with improved assessment of the peripheral segments because of the application of a contrast agent.

Factors affecting postoperative cerebrospinal fluid leaks after retrosigmoidal craniotomy for vestibular schwannomas

OBJECT The aim of this study was to identify patients likely to develop CSF leaks after vestibular schwannoma surgery using a retrospective analysis for the identification of risk factors. METHODS Between January 2001 and December 2006, 420 patients underwent retrosigmoidal microsurgical tumor removal in a standardized procedure. Of these 420 patients, 363 underwent treatment for the first time, and 27 suffered from recurrent tumors. Twenty-six patients had bilateral tumors due to neurofibromatosis Type 2, and 4 patients had previously undergone radiosurgical treatment. An analysis was performed to examine the incidence of postoperative CSF fistulas in all 4 groups. RESULTS The incidence of CSF leakage was higher in the tumor recurrence group (11.1%) than in patients undergoing surgery for the first time (4.4%). There were no CSF fistulas in the neurofibromatosis Type 2 group or in patients with preoperative radiosurgical treatment. Tumor size was identified as a possible risk factor in a previous study. CONCLUSIONS Surgery for recurrent tumors is a significant risk factor for the development of CSF leaks.

Bilateral malignant melanoma metastases to the internal auditory canal/cerebellopontine angle: surgical management and preservation of function

Although intracranial metastases of malignant melanomas are common, localization at the cerebellopontine angle (CPA) or in the internal auditory canal (IAC) is rare, and bilateral presentation especially so. We present the case of a 46-year-old Caucasian woman with bilateral IAC/CPA lesions and a prior history of malignant melanoma on the right leg. During preoperative investigations, the presence of the bilateral IAC/CPA lesions along with several radiologically identified lesions along the neural axis led to the suspicion that she had neurofibromatosis Type 2 despite her history of malignant melanoma and the lack of characteristic skin lesions and family history. Histopathological analysis of the resected lesion confirmed the intraoperative diagnosis of bilateral CPA malignant melanoma metastases. Surgical removal of the tumors via the retrosigmoid approach with preservation of normal bilateral facial nerve function and unilateral serviceable hearing, combined with control of the systemic disease, provided this patient with a near-normal quality of life for at least 42 months after the initial diagnosis of melanoma.