Bertrand Devaux

Subthalamic nucleus stimulation in severe obsessive-compulsive disorder.

BACKGROUND Severe, refractory obsessive-compulsive disorder (OCD) is a disabling condition. Stimulation of the subthalamic nucleus, a procedure that is already validated for the treatment of movement disorders, has been proposed as a therapeutic option. METHODS In this 10-month, crossover, double-blind, multicenter study assessing the efficacy and safety of stimulation of the subthalamic nucleus, we randomly assigned eight patients with highly refractory OCD to undergo active stimulation of the subthalamic nucleus followed by sham stimulation and eight to undergo sham stimulation followed by active stimulation. The primary outcome measure was the severity of OCD, as assessed by the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), at the end of two 3-month periods. General psychopathologic findings, functioning, and tolerance were assessed with the use of standardized psychiatric scales, the Global Assessment of Functioning (GAF) scale, and neuropsychological tests. RESULTS After active stimulation of the subthalamic nucleus, the Y-BOCS score (on a scale from 0 to 40, with lower scores indicating less severe symptoms) was significantly lower than the score after sham stimulation (mean [+/-SD], 19+/-8 vs. 28+/-7; P=0.01), and the GAF score (on a scale from 1 to 90, with higher scores indicating higher levels of functioning) was significantly higher (56+/-14 vs. 43+/-8, P=0.005). The ratings of neuropsychological measures, depression, and anxiety were not modified by stimulation. There were 15 serious adverse events overall, including 1 intracerebral hemorrhage and 2 infections; there were also 23 nonserious adverse events. CONCLUSIONS These preliminary findings suggest that stimulation of the subthalamic nucleus may reduce the symptoms of severe forms of OCD but is associated with a substantial risk of serious adverse events. (ClinicalTrials.gov number, NCT00169377.)

Intraspinal meningiomas: review of 54 cases with discussion of poor prognosis factors and modern therapeutic management.

INTRODUCTION Intraspinal meningiomas account for 25%-46% of primary spinal cord tumors. Technical advances in magnetic resonance imaging (MRI) and surgical procedures (ultrasonic cavitation aspirators [CUSA], lasers) have brought about better clinical results. In spite of these new techniques, a small percentage of patients still present with poor postoperative results and/or a recurrence. The authors tried to determine which data could influence clinical outcome and what therapeutic modalities could limit recurrence rate. MATERIALS AND METHODS We reviewed 54 patients who from 1963 to 1994, each had surgery for an intraspinal meningioma. There were 43 females and 11 males, aged 8 to 85 years old. Thirty-six (66.6%) patients were ambulatory on admission; only 2 presented with a paraplegia. Tumor location was cervical in 10 cases, thoracic in 43 cases, lumbar in 1 case. Forty-seven tumors were intradural, 5 epidural, 2 epidural and intradural. Thirty patients underwent a myelography, 10 a computed tomography (CT) scan, and 14 an MRI. Twenty-three spinal angiographies were performed before surgery. Complete removal was achieved in 50 patients (92.6%). Ultrasonic cavitation was used 10 times for debulking the tumor, and laser was used in 12 surgical procedures to perform hemostasis of the meningioma and to coagulate the dural attachment. RESULTS The majority of the neoplasms were meningothelial (N = 24) or psammomatous (N = 11). No mortality was noted. Morbidity concerned five patients: two pulmonary embolisms, one definitive paraplegia, one transient deficit, and one epidural suppuration, which necessitated a second operation. Mean follow-up was 28 months. Final functional results were very good in 85% and good in 13%; one patient (2%) worsened. Two recurrences were noted: one with clinical signs and the other with only CT-scan modifications. Both patients underwent complementary radiotherapy. DISCUSSION AND CONCLUSION The authors discuss factors influencing functional results. Sex, pregnancy, pathologic diagnosis, and recurrence do not seem to have any influence. Calcification of the meningioma, as well as an anterior dural attachment, are pejorative factors. They insist on preoperative angiography and point out the advantage of using a CUSA and/or a laser to debulk and coagulate the tumor itself and its dural attachment. They propose radiation therapy as an adjuvant treatment or an alternative to reoperation, which could be hazardous for some patients when, for instance, a recurrence is located in a critical area or when the patients general status is fragile.

Epileptic seizures in diffuse low-grade gliomas in adults

Diffuse low-grade gliomas are highly epileptogenic brain tumours. We aimed to explore the natural course of epileptic seizures, their predictors and the prognostic significance of their occurrence in adult patients harbouring a diffuse low-grade glioma. An observational retrospective multicentre study examined 1509 patients with diffuse low-grade gliomas to identify mutual interactions between tumour characteristics, tumour course and epileptic seizures. At diagnosis, 89.9% of patients had epileptic seizures. Male gender (P = 0.003) and tumour location within functional areas (P = 0.001) were independent predictors of a history of epileptic seizures at diagnosis. Tumour volume, growth velocity, cortical location, histopathological subtype or molecular markers did not significantly affect epileptic seizure occurrence probability. Prolonged history of epileptic seizures (P < 0.001), insular location (P = 0.003) and tumour location close to functional areas (P = 0.038) were independent predictors of uncontrolled epileptic seizures at diagnosis. Occurrence of epileptic seizures (P < 0.001), parietal (P = 0.029) and insular (P = 0.002) locations were independent predictors of uncontrolled epileptic seizures after oncological treatment. Patient age (P < 0.001), subtotal (P = 0.007) and total (P < 0.001) resections were independent predictors of total epileptic seizure control after oncological treatment. History of epileptic seizures at diagnosis and total surgical resection were independently associated with increased malignant progression-free (P < 0.001 and P < 0.001) and overall (P < 0.001 and P = 0.016) survivals. Epileptic seizures are independently associated with diffuse low-grade glioma prognosis. Patients diagnosed with epileptic seizures and those with complete and early surgical resections have better oncological outcomes. Early and maximal surgical resection is thus required for diffuse low-grade gliomas, both for oncological and epileptological purposes.

FDG-PET improves surgical outcome in negative MRI Taylor-type focal cortical dysplasias

Objective: To determine the diagnostic accuracy and prognostic value of 18FDG-PET in a recent series of patients operated for intractable partial epilepsy associated with histologically proven Taylor-type focal cortical dysplasia (TTFCD) and negative MRI. Methods: Of 23 consecutive patients (12 male, 7–38 years old) with negative 1.5-Tesla MRI, 10 exhibited subtle nonspecific abnormalities (e.g., unusual sulcus depth or gyral pattern) and the 13 others had strictly normal MRI. FDG-PET was analyzed both visually after coregistration on MRI and using SPM5 software. Metabolic data were compared with the epileptogenic zone (EZ) determined by stereo-EEG (SEEG) and surgical outcome. Results: Visual PET analysis disclosed a focal or regional hypometabolism in 18 cases (78%) corresponding to a single gyrus (n = 9) or a larger cortical region (n = 9). PET/MRI coregistration detected a partially hypometabolic gyrus in 4 additional cases. SPM5 PET analysis (n = 18) was concordant with visual analysis in 13 cases. Location of PET abnormalities was extratemporal in all cases, involving eloquent cortex in 15 (65%). Correlations between SEEG, PET/MRI, and histologic findings (n = 20) demonstrated that single hypometabolic gyri (n = 11) corresponded to EZ and TTFCD, which was localized at the bottom of the sulcus. Larger hypometabolic areas (n = 9) also included the EZ and the dysplastic cortex but were more extensive. Following limited cortical resection (mean follow-up 4 years), seizure freedom without permanent motor deficit was obtained in 20/23 patients (87%). Conclusions: 18FDG-PET coregistered with MRI is highly sensitive to detect TTFCD and greatly improves diagnosis and surgical prognosis of patients with negative MRI.

Diffuse low-grade oligodendrogliomas extend beyond MRI-defined abnormalities

Background: Imaging determinations of the spatial extent of diffuse low-grade gliomas (DLGGs) are of paramount importance in evaluating the risk-to-benefit ratio of surgical resection. However, it is not clear how accurately preoperative conventional MRI can delineate DLGGs. Methods: We report a retrospective histologic and imaging correlation study in 16 adult patients who underwent serial stereotactic biopsies for the diagnosis of untreated supratentorial well-defined and non–contrast-enhanced DLGG, in whom biopsy samples were taken within and beyond (OutBSs) MRI-defined abnormalities. Results: Thirty-seven OutBSs that extended from 10 to 26 mm beyond MRI-defined abnormalities were studied. Immunostaining revealed MIB-1–positive cells (i.e., cycling cells) in all but 2 of the OutBSs. None of the MIB-1–positive cells coexpressed glial fibrillary acidic protein, and all of them coexpressed OLIG2. MIB-1–positive cells were cycling isolated tumor cells, because 1) their morphologic characteristics reflected those of tumor cells, 2) the number of MIB-1–positive cells per square centimeter was significantly higher than that of controls, 3) the number of MIB-1–positive cells per square centimeter was positively correlated with the tumor growth fraction (p = 0.012), and 4) the number of MIB-1–positive cells per square centimeter in OutBSs decreased with distance from the tumor (p = 0.003). Conclusions: This study demonstrates, using a multiscale correlative approach, that conventional MRI underestimates the actual spatial extent of diffuse low-grade gliomas (DLGGs), even when they are well delineated. These results suggest that an extended resection of a margin beyond MRI-defined abnormalities, whenever feasible in noneloquent brain areas, might improve the outcome of DLGGs.

Type II focal cortical dysplasia: electroclinical phenotype and surgical outcome related to imaging.

Purpose:  Type II focal cortical dysplasia (TTFCD), a highly epileptogenic lesion with severe epilepsy curable by surgery, is missed by magnetic resonance imaging (MRI) in about one third of cases. Little is known about the electroclinical presentation in these MRI‐negative patients and a poor surgical outcome is frequently reported. We compared the clinical and neurophysiologic features in MRI‐negative and MRI‐positive cases in order to better identify candidates for surgery.

Imaging of non-tumorous and tumorous human brain tissues with full-field optical coherence tomography☆

A prospective study was performed on neurosurgical samples from 18 patients to evaluate the use of full-field optical coherence tomography (FF-OCT) in brain tumor diagnosis. FF-OCT captures en face slices of tissue samples at 1 μm resolution in 3D to a penetration depth of around 200 μm. A 1 cm2 specimen is scanned at a single depth and processed in about 5 min. This rapid imaging process is non-invasive and requires neither contrast agent injection nor tissue preparation, which makes it particularly well suited to medical imaging applications. Temporal chronic epileptic parenchyma and brain tumors such as meningiomas, low-grade and high-grade gliomas, and choroid plexus papilloma were imaged. A subpopulation of neurons, myelin fibers and CNS vasculature were clearly identified. Cortex could be discriminated from white matter, but individual glial cells such as astrocytes (normal or reactive) or oligodendrocytes were not observable. This study reports for the first time on the feasibility of using FF-OCT in a real-time manner as a label-free non-invasive imaging technique in an intraoperative neurosurgical clinical setting to assess tumorous glial and epileptic margins.

Intralesional recordings and epileptogenic zone in focal polymicrogyria

Purpose: Polymicrogyria (PMG) is recognized as an epileptogenic lesion but few data concerning organization of the epileptogenic zone (EZ) are available.

Diagnostic methods and treatment options for focal cortical dysplasia.

Our inability to adequately treat many patients with refractory epilepsy caused by focal cortical dysplasia (FCD), surgical inaccessibility and failures are significant clinical drawbacks. The targeting of physiologic features of epileptogenesis in FCD and colocalizing functionality has enhanced completeness of surgical resection, the main determinant of outcome. Electroencephalography (EEG)–functional magnetic resonance imaging (fMRI) and magnetoencephalography are helpful in guiding electrode implantation and surgical treatment, and high‐frequency oscillations help defining the extent of the epileptogenic dysplasia. Ultra high‐field MRI has a role in understanding the laminar organization of the cortex, and fluorodeoxyglucose–positron emission tomography (FDG‐PET) is highly sensitive for detecting FCD in MRI‐negative cases. Multimodal imaging is clinically valuable, either by improving the rate of postoperative seizure freedom or by reducing postoperative deficits. However, there is no level 1 evidence that it improves outcomes. Proof for a specific effect of antiepileptic drugs (AEDs) in FCD is lacking. Pathogenic mutations recently described in mammalian target of rapamycin (mTOR) genes in FCD have yielded important insights into novel treatment options with mTOR inhibitors, which might represent an example of personalized treatment of epilepsy based on the known mechanisms of disease. The ketogenic diet (KD) has been demonstrated to be particularly effective in children with epilepsy caused by structural abnormalities, especially FCD. It attenuates epigenetic chromatin modifications, a master regulator for gene expression and functional adaptation of the cell, thereby modifying disease progression. This could imply lasting benefit of dietary manipulation. Neurostimulation techniques have produced variable clinical outcomes in FCD. In widespread dysplasias, vagus nerve stimulation (VNS) has achieved responder rates >50%; however, the efficacy of noninvasive cranial nerve stimulation modalities such as transcutaneous VNS (tVNS) and noninvasive (nVNS) requires further study. Although review of current strategies underscores the serious shortcomings of treatment‐resistant cases, initial evidence from novel approaches suggests that future success is possible.

Differential Proteomic Analysis of Human Glioblastoma and Neural Stem Cells Reveals HDGF as a Novel Angiogenic Secreted Factor

Presence in glioblastomas of cancer cells with normal neural stem cell (NSC) properties, tumor initiating capacity, and resistance to current therapies suggests that glioblastoma stem‐like cells (GSCs) play central roles in glioblastoma development. We cultured human GSCs endowed with all features of tumor stem cells, including tumor initiation after xenograft and radio‐chemoresistance. We established proteomes from four GSC cultures and their corresponding whole tumor tissues (TTs) and from human NSCs. Two‐dimensional difference gel electrophoresis and tandem mass spectrometry revealed a twofold increase of hepatoma‐derived growth factor (HDGF) in GSCs as compared to TTs and NSCs. Western blot analysis confirmed HDGF overexpression in GSCs as well as its presence in GSC‐conditioned medium, while, in contrast, no HDGF was detected in NSC secretome. At the functional level, GSC‐conditioned medium induced migration of human cerebral endothelial cells that can be blocked by anti‐HDGF antibodies. In vivo, GSC‐conditioned medium induced neoangiogenesis, whereas HDGF‐targeting siRNAs abrogated this effect. Altogether, our results identify a novel candidate, by which GSCs can support neoangiogenesis, a high‐grade glioma hallmark. Our strategy illustrates the usefulness of comparative proteomic analysis to decipher molecular pathways, which underlie GSC properties. STEM CELLS 2012;30:845–853