Clinical, radiological and molecular characterization of intramedullary astrocytomas.

Intramedullary astrocytomas (IMAs) are rare tumors, and few studies specific to the molecular alterations of IMAs have been performed. Recently, KIAA1549-BRAF fusions and the H3F3A p.K27M mutation have been described in low-grade (LG) and high-grade (HG) IMAs, respectively. In the present study, we collected clinico-radiological data and performed targeted next-generation sequencing for 61 IMAs (26 grade I pilocytic, 17 grade II diffuse, 3 LG, 3 grade III and 12 grade IV) to identify KIAA1549-BRAF fusions and mutations in 33 genes commonly implicated in gliomas and the 1p/19q regions. One hundred seventeen brain astrocytomas were analyzed for comparison. While we did not observe a difference in clinico-radiological features between LG and HG IMAs, we observed significantly different overall survival (OS) and event-free survival (EFS). Multivariate analysis showed that the tumor grade was associated with better OS while EFS was strongly impacted by tumor grade and surgery, with higher rates of disease progression in cases in which only biopsy could be performed. For LG IMAs, EFS was only impacted by surgery and not by grade. The most common mutations found in IMAs involved TP53, H3F3A p.K27M and ATRX. As in the brain, grade I pilocytic IMAs frequently harbored KIAA1549-BRAF fusions but with different fusion types. Non-canonical IDH mutations were observed in only 2 grade II diffuse IMAs. No EGFR or TERT promoter alterations were found in IDH wild-type grade II diffuse IMAs. These latter tumors seem to have a good prognosis, and only 2 cases underwent anaplastic evolution. All of the HG IMAs presented at least one molecular alteration, with the most frequent one being the H3F3A p.K27M mutation. The H3F3A p.K27M mutation showed significant associations with OS and EFS after multivariate analysis. This study emphasizes that IMAs have distinct clinico-radiological, natural evolution and molecular landscapes from brain astrocytomas.

Establishment of the Military Neurosurgeons Committee within the World Federation of Neurosurgical Societies.

In 2009, during the World Congress of Neurological Surgery in Boston, Massachusetts, the World Federation of Neurosurgical Societies (WFNS) Executive Committee decided to establish a Military Neurosurgeons Committee. A separate scientific session on military neurosurgery was held at the next WFNS Interim Meeting in September 2011 in Brazil. A further separate session on military neurosurgery will take place at the next WFNS Meeting in Seoul, South Korea.

Long-term follow-up survey reveals a high yield, up to 30% of patients presenting newly detected aneurysms more than 10 years after ruptured intracranial aneurysms clipping.

The need to pursue long-term follow-up in patients treated for a ruptured aneurysm remains debated. New aneurysms development is a crucial element to consider but remains scarcely analyzed especially after a mean follow-up longer than 10 years. Our study was designed to provide rates of newly developed aneurysms in patients who have undergone prior clipping who were not followed with serial imaging. Patients were included if they were (1) treated more than 10 years ago by clipping of a ruptured aneurysm, (2) independent at time of discharge, (3) presently younger than 65 years, and if (4) they agreed to undergo a late digital subtraction angiography (DSA) control or to transmit results of a recent one performed elsewhere. Twenty patients were included with a mean delay between aneurysm treatment and late DSA of 18.0 years (10-26.5 years). Out of these patients, six (30%) harbored new aneurysms. Of these six individuals, four (66.6%) presented multiple aneurysms with a total of 15 newly discovered aneurysms. Aneurysm sizes ranged from 1 to 10 mm. One patient suffered from a de novo aneurysm rupture. Multiple aneurysms at the time of the first hemorrhage were a risk factor in developing de novo aneurysm (p=0.0175). In conclusion, based on a 30% rate of new aneurysm formation in patients clipped more than a decade ago, close screening on a very long-term perspective is encouraged. This study suggests aneurysm formation to be a continuous process.

Management of anterolateral foramen magnum meningiomas: surgical vs conservative decision making.

BACKGROUND: Anterolateral meningiomas of the foramen magnum (FMMs) represent a neurosurgical challenge because they grow in close contact with osteoarticular, nervous, and vascular structures that cannot be sacrificed or retracted. OBJECTIVE: To evaluate our strategy and results in 26 patients with FMMs and analyze factors affecting the decision-making process, resection, and outcome. METHODS: Among 26 consecutive symptomatic FMM (10 anterior, 16 lateral) patients (16 women, 10 men, ages 28-82 years), 4 older than 70 years of age were untreated. Twenty-two were operated on using a posterolateral approach, with the vertebral artery transposed in 19 and the occipital condyle drilled in 10. We analyzed the characteristics and outcome of untreated cases, the utility of THE occipital condyle drilled, the difficulties of microdissection, morbidity and total removal rates, the outcome of tumor residues, and the literature on radiosurgery. RESULTS: Three of 4 untreated patients remained clinically stable at 2 to 5 years. After systematic vertebral artery medial transposition and occipital condyle drilled in 6 cases, our technique evolved with experience in the next 16 (vertebral artery transposed in 13 of 16; occipital condyle drilled in 4 of 13) for dissecting anteriorly beyond midline (anterior FMMs). Retrocondylar access was sufficient for lateral FMMs. Tumors were totally removed in 16 of 22 (73%). One patient died, and 4 had permanent deficits. Follow-up of more than 5 years in 12 patients showed no C0-1 instability, and slight increase of tumor residue size 7 years after surgery. In the literature, 15 FMMs treated with radiosurgery are reported, 13 at diagnosis and 2 at recurrence, with short-term clinical and radiological safety and efficacy. CONCLUSION: We currently recommend (1) aiming for subtotal removal in difficult cases, (2) remaining conservative in asymptomatic or elderly patients with mild symptoms, and (3) considering radiosurgery at diagnosis for small (<30 mm) symptomatic FMMs or as an adjunct for evolving residues/recurrences in poor candidates for resection.

Clinical interest of integrating positron emission tomography imaging in the workup of 55 children with incidentally diagnosed brain lesions.

OBJECT: In this paper, the authors' goal was to evaluate the impact of PET data on the clinical management of incidental brain lesions in children. METHODS: Between 1995 and 2007, 442 children with a newly diagnosed brain lesion were referred to the authors' department. Of these, 55 presented with an incidental brain lesion and were selected for study because MR imaging sequences revealed limitations in assessing the tumor, its evolving nature, and/or the malignant potential of the lesion diagnosed. Thirteen children were studied using FDG-PET and 42 with L-(methyl-(11)C)-methionine (MET)-PET; 3 children underwent both FDG-PET and MET-PET but only the MET-PET results were used in the analysis. The PET and MR images were combined in image fusion navigation planning. Drawing on their experience with PET in adults, the authors proposed the following treatment plans: 1) surgery in children with imaging evidence of increased PET tracer uptake, which is highly specific of tumor and/or malignant tumor tissue; or 2) conservative treatment in children in whom there was little or no tracer uptake on PET. The authors compared the PET data with the MR imaging-based diagnosis and either 1) the results of histological examination in surgically treated cases, or 2) the long-term outcome in untreated cases. They studied PET and MR imaging sensitivity and specificity in detecting tumor and malignant tissues, and evaluated whether PET data altered their clinical management. RESULTS: Seventeen children had increased PET tracer uptake and underwent surgery. Tumor diagnosis was confirmed in all cases (that is, there were no false-positive findings). Cases in which there was little or no PET tracer uptake supported conservative treatment in 38 children. However, because PET was under evaluation, 16 of 38 lesions that were judged accessible for resection were surgically treated. Histological examination results demonstrated neither malignant nor evolving tumor tissue but yielded 9 indolent tumors (6 dysembryoplastic neuroectodermal tumors, 2 low-grade astrocytomas, and 1 low-grade astrocytoma and dysplasia) and 7 nontumoral lesions (3 cases of vasculitis, 3 of gliosis, and 1 of sarcoidosis). In 22 of the untreated 38 children, stable disease was noted during follow-up (range 18-136 months). Although an absence of PET tracer uptake might not exclude tumor tissue, PET did not reveal any false-negative findings in malignant or evolving tumor tissue detection in cases in which MR imaging showed false-positive and -negative cases in > 35 and 25% of the cases, respectively. CONCLUSIONS: These data confirmed the high sensitivity and specificity of PET to detect tumor as well as malignant tissue. Regarding the treatment of the incidental brain lesions, the PET findings enabled the authors to make more appropriate decisions regarding treatment than those made on MR imaging findings alone. Therefore, the risk of surgically treating a nontumoral lesion was reduced as well as that for conservatively managing a malignant tumor. Nowadays, it is estimated that these data justify conservative management in incidental lesions with low or absent PET tracer uptake.

Clinical impact of integrating positron emission tomography during surgery in 85 children with brain tumors.

OBJECT: In this paper, the authors' goal was to evaluate the impact of PET information on brain tumor surgery in children. METHODS: Between 1995 and 2007, 442 children were referred to the authors' institution for a newly diagnosed brain lesion. Of these, 85 were studied with FDG-PET and/or L-(methyl-(11)C)-methionine -PET in cases in which MR images were unable to assist in selecting accurate biopsy targets (35 patients) or to delineate tumors for maximal resection (50 patients). In surgical cases, PET and MR images were combined in image fusion planning for stereotactic biopsies or navigation-based resections. The preoperative planning images were compared postoperatively with MR imaging and PET findings and histological data for evaluating the clinical impact on the diagnostic yield and tumor resection. RESULTS: The PET data influenced surgical decisions or procedures in all cases. The use of PET helped to better differentiate indolent from active components in complex lesions (in 12 patients); improved target selection and diagnostic yield of stereotactic biopsies without increasing the sampling; provided additional prognostic information; reduced the amount of tissue needed for biopsy sampling in brainstem lesions (in 20 cases); better delineated lesions that were poorly delineated on MR imaging and that infiltrated functional cortex (in 50 cases); significantly increased the amount of tumor tissue removed in cases in which total resection influenced survival (in 20 cases); guided resection in hypermetabolic areas (in 15 cases); improved early postoperative detection of residual tumor (in 20 cases); avoided unnecessary reoperation (in 5 cases); and supported the decision to undertake early second-look resection (in 8 cases). CONCLUSIONS: The authors found that PET has a significant impact on the surgical decisions and procedures for managing pediatric brain tumors. Further studies may demonstrate whether PET improves outcomes in children.

Preliminary personal experiences with the application of near-infrared indocyanine green videoangiography in extracranial vertebral artery surgery.

INTRODUCTION: We evaluated the feasibility, usefulness, and limitations of near-infrared indocyanine green (ICG) videoangiography during procedures involving the extracranial vertebral artery (VA). METHODS: Nine patients (2 women, 7 men; mean age, 55 years) were evaluated at 2 neurosurgical centers. Near-infrared ICG videoangiography was applied during transposition and rerouting of the first segment of VA (V1; n = 6) and during resection of neurinomas near the second (V2; n = 1) and third (V3; n = 2) segments of VA. RESULTS: Early after ICG injection, V1 fluoresced homogenously. The fluorescence of V2 and V3 varied. Without extrinsic compression, these segments appeared as noncontiguous hot spots because the VA runs freely in a periosteal sheath surrounded by a venous plexus that attenuates the fluorescent light. Hot spots corresponded to areas where the artery neared the surface. With extrinsic compression, VA enhanced homogenously because it was pushed against the periosteal layer. During the late phase, the V1 signal was attenuated, whereas the venous plexus surrounding V2 and V3 enhanced homogeneously, thereby masking the VA itself. Near-infrared ICG videoangiography helped to confirm VA patency during transposition and rerouting but was not helpful during VA exposure because the periosteal sheath must already be exposed to detect the VA or its surrounding plexus. After exposure, videoangiography can help to determine the position of the VA within its periosteal sheath. CONCLUSION: Videoangiography can be used to provide information about the patency of the VA and its location within the periosteal sheath to prevent injury during resection of tumor adherent to the periosteal sheath.

Reversible neurochemical changes mediated by delayed intrastriatal glial cell line-derived neurotrophic factor gene delivery in a partial Parkinson's disease rat model.

BACKGROUND: Efficient protection of dopaminergic neurons against a subsequent 6-hydroxydopamine lesion by glial cell line-derived neurotrophic factor (GDNF) gene delivery has been demonstrated. By contrast, the neurorestorative effects of GDNF administered several weeks after the toxin have been less characterized. In particular, whether these were permanent or dependent on the continuous presence of GDNF remains elusive. METHODS: A tetracycline-inducible adeno-associated virus (AAV)-1 vector expressing human GDNF cDNA was administered unilaterally in the rat striatum 5 weeks after 6-hydroxydopamine. Rats were treated with doxycycline (dox) or untreated from the day of vector injection until sacrifice (4 or 14 weeks). A sub-group was dox-treated for 7 weeks then untreated until 14 weeks. The motor behavior was assessed by amphetamine-induced rotations and spontaneous forelimb asymmetry. The amounts of tyrosine hydroxylase (TH), serine-40-phosphorylated TH (S40-TH) and aromatic amino acid decarboxylase (AADC) proteins were compared by western blotting and the dopamine levels quantified by high-performance liquid chromatography. RESULTS: Dox-dependent behavioral improvements were demonstrated 4 weeks post-vector injection. At later time points, spontaneous partial recovery was observed in all rats, but no further improvement was found in dox-treated animals. TH levels were significantly increased in dox-treated rats at all time points. By contrast, striatal dopamine and S40-TH were increased at 4 weeks, but not 14 weeks, and AADC remained unchanged. Dox withdrawal after 7 weeks, resulted in TH levels comparable to the controls at 14 weeks. CONCLUSIONS: Delayed GDNF gene delivery only transiently improved dopaminergic function. Over the long term, TH was more abundant, but not functional, and the increase was lost when GDNF gene expression was switched off.

Positron emission tomography-guided volumetric resection of supratentorial high-grade gliomas: a survival analysis in 66 consecutive patients.

OBJECTIVE: Integrating positron emission tomographic (PET) images into the image-guided resection of high-grade gliomas (HGG) has shown that metabolic information on tumor heterogeneity and distribution are useful for planning surgery, improve tumor delineation, and provide a final target contour different from that obtained with magnetic resonance imaging (MRI) alone in about 80% of the procedures. Moreover, PET guidance helps to increase the amount of tumor removed and to target image-guided resection to anaplastic tissue areas. The present study aims to evaluate whether PET-guided volumetric resection (VR) in supratentorial HGG might add benefit to the patient's outcome. METHODS: PET images using [18F]fluorodeoxyglucose (n=23) and [11C]methionine (n=43) were combined with MRI scans in the planning of VR procedures performed at the initial stage in 66 consecutive patients (43 M/23 F) with supratentorial HGG according to the technique previously described. In all cases (35 anaplastic gliomas [20 astrocytomas, 10 oligoastrocytomas, 5 oligodendrogliomas] and 31 glioblastomas [GBM]), level and distribution of PET tracer uptake were analyzed to define a PET contour projected on MRI scans to define a final target contour for VR. Maximal tumor resection was accomplished in each case, with the intention to remove the entire abnormal metabolic area comprised in the surgical planning. Early postoperative MRI and PET assessed tumor resection. Survival analysis was performed separately in anaplastic gliomas and glioblastoma multiforme according to the presence or absence of residual tracer uptake on postoperative PET and according to the presence or absence of residual contrast enhancement on postoperative MRI. RESULTS: Preoperatively, metabolic information helped the surgical planning. In all procedures, PET contributed to define a final target contour different from that obtained with MRI alone. Postoperatively, 46 of 66 patients had no residual PET tracer uptake (total PET resection), 23 of 66 had no residual MRI contrast enhancement. No additional neurological morbidity due to the technique was reported. A total PET tracer uptake resection was associated with a significantly longer survival in anaplastic gliomas (P = 0.0071) and in glioblastoma multiforme (P = 0.0001), respectively. A total MRI contrast enhancement resection was not correlated with a significantly better survival, neither in anaplastic gliomas (P = 0.6089) nor in glioblastoma multiforme (P = 0.6806). CONCLUSIONS: Complete resection of the increased PET tracer uptake prolongs the survival of HGG patients. Because PET information represents a more specific marker than MRI enhancement for detecting anaplastic tumor tissue, PET-guidance increases the amount of anaplastic tissue removed in HGG.

Brain stem metastases treated with radiosurgery: prognostic factors of survival and life expectancy estimation.

BACKGROUND: The objective of this study is to study prognostic factors of survival and 3 stratification systems for life expectancy estimation in patients with brain stem metastases treated with radiosurgery. METHODS: Between December 1999 and November 2006, 25 patients with 27 brain stem metastases were treated with Gamma Knife radiosurgery. The lesions' mean volume was 0.6 mL (0.013-3.6 mL). The mean marginal dose was 20 Gy (15-24 Gy). Univariate and multivariate studies were done to identify prognostic factors, and 3 patient stratification systems were applied for survival estimation: RPA, SIR, and BSBM. RESULTS: The primary tumor location was in the lungs in 12 patients, breast in 8, and other in 5. Fourteen lesions were located in the pons, 9 in the midbrain, and 4 in the medulla. All patients were followed clinically. Radiologic follow-up was available in 21 lesions (78%). Tumor control was achieved in all but one followed lesion (95%). There were no complications related to treatment. Median survival of patients with brain stem metastases was 11.1 months. In multivariate analysis, KPS of 80 or more, control of the primary tumor, absence of radiotherapy, and a marginal dose higher than 18 Gy were associated with better survival. The BSBM in the univariate and multivariate analyses was the strongest predictor of survival (P < .0001). CONCLUSIONS: The BSBM was the most useful tool for estimating survival. Rather than the brain stem location of an intracranial metastasis, the patient integral clinical status seems to be more important in determining survival.

Combination of functional magnetic resonance imaging-guided neuronavigation and intraoperative cortical brain mapping improves targeting of motor cortex stimulation in neuropathic pain.

OBJECTIVE: To evaluate, regardless of the clinical results, the contribution of combining functional magnetic resonance imaging (fMRI) with intraoperative cortical brain mapping (iCM) as functional targeting methods for epidural chronic motor cortex stimulation (MCS) in refractory neuropathic pain. METHODS: Eighteen neuropathic pain patients (central stroke in six; trigeminal neuropathy in six; syrinx or amputation in six) who underwent operations for epidural MCS were studied with preoperative fMRI and iCM. fMRI investigated motor tasks of hands (as well as foot and tongue, when painful). fMRI data were analyzed with Statistical Parametric Mapping99 software (University College London, London, England; initial analysis threshold corresponding to P < 0.001), registered in a neuronavigation system, and correlated during surgery with iCM. The primary aim of this study was to improve the topographical precision of MCS. Matching of fMRI and iCM specifically was examined. RESULTS: Correspondence between the contour of the fMRI activation area and iCM in precentral gyrus (mean distance, 3.8 mm) was found in 17 (94%) of 18 patients. Eleven of them showed correspondence for more restrictive values of the analysis threshold (P < 0.0001); in six patients, the quality of the iCM was reduced by somatosensory wave attenuation and general anesthesia. In this group of six patients, a combination of both techniques was used for the final targeting. Correspondence was not found in one patient as the result of image distortion and residual motion artifact. At follow-up (4-60 mo), MCS induced significant pain relief in a total of 11 patients (61%). CONCLUSION: This study confirms the functional accuracy of fMRI guidance in neuropathic pain and illustrates the usefulness of combining fMRI guidance with iCM to improve the functional targeting in MCS. Because appropriate targeting is crucial to obtaining pain relief, this combination may increase the analgesic efficacy of MCS.

Preliminary experience with the enterprise stent for endovascular treatment of complex intracranial aneurysms: potential advantages and limiting characteristics.

OBJECTIVE: Stent-assisted coiling is an accepted endovascular treatment (EVT) for complex intracranial aneurysms. The Enterprise self-expandable stent (Cordis, Miami Lakes, FL) is a new retractable stent that is delivered via a conventional coiling catheter to potentially circumvent the limitations of other stents. The aim of this study was to evaluate the use of this stent for EVT of complex aneurysms. METHODS: Between January and May 2007, 14 patients with 15 unruptured wide-necked or fusiform aneurysms were treated. EVT consisted of stent placement and subsequent endosaccular coiling. Clinical outcome was assessed with the modified Glasgow Outcome Scale. RESULTS: EVT was successfully performed and led to an excellent outcome in all patients. The stent was easily navigated and precisely positioned in all cases. However, the stent's visibility was poor once it was delivered. Moreover, procedural complications occurred in three patients, including stent migration (n = 1) and coil protrusion between the stent and the vessel wall (n = 2). In these latter two cases, a remodeling balloon was required to assist in delivery of the coils. No clinical incidence of complications was observed when the parent artery had a diameter of more than 4 mm. Angiographic results consisted of eight complete occlusions, four neck remnants, and three incomplete occlusions. CONCLUSION: The Enterprise stent is very useful for EVT of complex intracranial aneurysms because it is easy to navigate and place precisely. However, the currently available stent has two relatively limiting characteristics: 1) it has poor visibility, and 2) it should only be used for aneurysms located on a parent artery with a maximal diameter of 4 mm.

Neurovascular compression anatomy and pain outcome in patients with classic trigeminal neuralgia treated by radiosurgery.

OBJECTIVE: To study the influence of the anatomy of neurovascular compression (NVC) on pain outcome in patients with classic trigeminal neuralgia treated by radiosurgery. METHODS: Analysis of the anatomy of the trigeminal nerve, brainstem, and vessels was performed in 89 consecutive patients treated by Leksell gamma knife (Elekta Instruments, Stockholm, Sweden) for classic trigeminal neuralgia. One-millimeter axial magnetic resonance imaging slices (T1-weighted, T1-weighted enhanced, and T2-weighted selected partial inversion recovery) with coronal, sagittal, and three-dimensional reconstructions were viewed. The end point for outcome was total pain remission and no medication. The follow-up period ranged between 6 and 42 months. RESULTS: In 82 patients (92%), a vascular structure in contact with the nerve was observed. In four patients, the NVC was produced by a large vessel (basilar or vertebral artery) and in 78 by a smaller vessel. The superior cerebellar artery was the cause of the NVC in 64 patients (78%). The NVC was proximal (<3 mm to the brainstem) in 34 patients (41%) and distal in 43 patients (52%). Nerve dislocation was present in 29 patients (33%), and nerve atrophy was present in 21 (24%) patients. Visualization of NVC on magnetic resonance imaging scans was not associated with outcome. The two variables associated with poor outcome were a large vessel contacting the nerve with brainstem deformation and proximal NVC. Nerve atrophy and nerve dislocation were not associated with outcome. CONCLUSION: The visualization of NVC, nerve atrophy, and nerve dislocation on magnetic resonance imaging scans was not associated with pain outcome. A large vessel compressing the nerve and deforming the brainstem and proximal NVC were associated with a lesser pain control.

Circumferential and fusiform intracranial aneurysms: reconstructive endovascular treatment with self-expandable stents.

INTRODUCTION: We report our experience with endovascular treatment (EVT) of circumferential and fusiform intracranial aneurysms by a reconstructive approach with self-expandable stents. METHODS: A retrospective review of our prospectively maintained database identified all circumferential and fusiform aneurysms treated by a reconstructive endovascular approach over a 3-year period. Clinical charts, procedural data, and angiographic results were reviewed. RESULTS: From April 2004 to May 2007, 13 patients were identified, of whom 12 were asymptomatic and 1 presented with a subarachnoid hemorrhage. Two patients with an aneurysm

Recombinant AAV viral vectors serotype 1, 2, and 5 mediate differential gene transfer efficiency in rat striatal fetal grafts.

Intrastriatal grafts of fetal ganglionic eminences (GE) can reverse symptoms of striatal lesions in animal models of Huntington's disease. On the other hand, neurotrophic factors have been shown to protect host striatal neurons from ongoing degeneration. Neurotrophic gene transfer into GE prior to grafting could combine the benefits of striatal neuron replacement and in situ delivery of neurotrophic factors. Here we evaluate the potency of recombinant adeno-associated viruses (rAAV) as vectors for gene delivery into rat embryonic (E15) GE using the eGFP reporter gene under the control of the strong cytomegalovirus (CMV) promoter. We observed a very efficient expression of the eGFP reporter gene in organotypic cultures of GE infected with rAAV serotype 1 from 4 days until at least 4 weeks postinfection. In contrast, transduction was low and absent when using serotype 2 and serotype 5 rAAV, respectively. Two months after transplantation of rAAV2/1-infected embryonic GE in adult rat striatum, more than 20% of grafted cells expressed eGFP. The majority of transduced cells in the graft were neurons as indicated by colabeling of GFP-immunoreactive cells with the NeuN marker. Our study suggests that GE transduced by rAAV-serotype 1 vectors could be an interesting tool to mediate efficient expression of a gene coding a neurotrophic factor in Huntington's disease.