Marc Levivier

Core assessment program for surgical interventional therapies in Parkinson's disease (CAPSIT-PD).

In 1992 the Core Assessment Program for Intracerebral Transplantations (CAPIT) was published providing the minimal requirements for a common patient evaluation protocol. Despite the intent, the program was thought to be too laborious to carry out in large scale trials, and it also lacked evaluations of cognitive functions and quality of life. Moreover, the CAPIT was designed for neural transplantation only and has not been revised since. Since then, pallidotomy and deep brain stimulation have emerged as additional treatment modalities but there exists no common tool for evaluation of, and between, the techniques. In 1996, within the framework of NECTAR (Network for European CNS Transplantation and Restoration), a dedicated program entitled “Neurosurgical Interventions in Parkinsons Disease” (NIPD) was funded by the European Union Biomed 2 program to develop a new Core Assessment Program for Surgical Interventional Therapies in PD (CAPSIT‐PD) and to establish an European registry for patients with PD subjected to functional neurosurgery. This article presents the recommendations of this new program.

Neural transplantation for the treatment of Parkinson's disease

trials showed unequivocally that human fetal dopaminergicneurons can survive and function for more than 10 years inthe striatum of patients with PD and show no signs of beingaffected by the ongoing disease process. These studies have also provided a clear indication that grafted fetaldopaminergic neurons can be therapeutically effective. On thebasis of the limited, but encouraging, observations in theseearly open-label trials,

Recombinant AAV-mediated gene delivery to the central nervous system

Various regions of the brain have been successfully transduced by recombinant adeno‐associated virus (rAAV) vectors with no detected toxicity. When using the cytomegalovirus immediate early (CMV) promoter, a gradual decline in the number of transduced cells has been described. In contrast, the use of cellular promoters such as the neuron‐specific enolase promoter or hybrid promoters such as the chicken β‐actin/CMV promoter resulted in sustained transgene expression. The cellular tropism of rAAV‐mediated gene transfer in the central nervous system (CNS) varies depending on the serotype used. Serotype 2 vectors preferentially transduce neurons whereas rAAV5 and rAAV1 transduce both neurons and glial cells. Recombinant AAV4‐mediated gene transfer was inefficient in neurons and glial cells of the striatum (the only structure tested so far) but efficient in ependymal cells.

Regional glucose metabolism and histopathology of gliomas: A study based on positron emission tomography‐guided stereotactic biopsy

Positron emission tomography (PET) with 18F‐2‐fluoro‐2‐deoxy‐D‐glucose (FDG) is widely applied to the study of gliomas. The histology of most gliomas is regionally heterogeneous. The relationship between histologic features and glucose metabolism evaluated by PET with FDG may therefore vary within the limits of the tumor. PET with FDG integrated in the planning of stereotactic brain biopsy allows precise comparison between local FDG uptake and histology. Using this approach, the authors investigated whether glucose metabolism of gliomas is related to anaplasia, and whether PET with FDG detects metabolic heterogeneity that parallels histologic heterogeneity of gliomas.

Statistical parametric mapping of regional glucose metabolism in mesial temporal lobe epilepsy.

We investigated statistical parametric mapping (SPM) use for positron emission tomography (PET) with [(18)F]fluorodeoxyglucose (FDG) data analysis in mesial temporal lobe epilepsy. The study involved 14 patients with temporal lobe epilepsy ultimately treated by anterior temporal lobectomy. Surgical outcome in terms of seizure control was favorable in 12 patients. Two different SPM approaches were designed to analyze each FDG-PET scan: a direct comparison with a control group (n = 27) and a search for significant interhemispheric asymmetry considering the asymmetry existing in the control group. Statistical inference was performed, first, without correction for multiple comparisons (making the hypothesis of temporal hypometabolism) and, second, after correction for multiple comparisons. Search for temporal interhemispheric asymmetry under the hypothesis of temporal hypometabolism was the most reliable SPM approach: hypometabolism was identified on the side chosen for resection in most cases (sensitivity, 71%; specificity, 100%) and was predictive of favorable postsurgical outcome in 90% of the patients. There was no false-positive result within the control group using this approach. After correction for multiple comparisons, SPM also identified in some patients temporal hypermetabolic areas as well as extratemporal cortical and subcortical hypometabolic areas on the side of resection but also on the contralateral side. In a further step, SPM was used for a group analysis of patients with favorable outcome after reversing scans when needed to set an identical lateralization in all patients. This analysis identified multiple ipsilateral temporal and extratemporal hypometabolic regions; when temporal metabolic changes were specifically assessed, the contralateral mesiotemporal region was found hypermetabolic, possibly as a manifestation of compensatory mechanisms in the presence of a unilateral epileptogenic lesion.

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

OBJECTIVEIntegrating 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 patients outcome. METHODSPET 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. RESULTSPreoperatively, 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). CONCLUSIONSComplete 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.

Tetracycline-inducible transgene expression mediated by a single AAV vector

Regulated gene delivery systems are usually made of two elements: an inducible promoter and a transactivator. In order to optimize gene delivery and regulation, a single viral vector ensuring adequate stoichiometry of the two elements is required. However, efficient regulation is hampered by interferences between the inducible promoter and (i) the promoter used to express the transactivator and/or (ii) promoter/enhancer elements present in the viral vector backbone. We describe a single AAV vector in which transcription of both the reverse tetracycline transactivator (rtTA) and the transgene is initiated from a bidirectional tetracycline-responsive promoter and terminated at bidirectional SV40 polyadenylation sites flanking both ITRs. Up to 50-fold induction of gene expression in human tumor cell lines and 100-fold in primary cultures of rat Schwann cells was demonstrated. In addition an 80-fold induction in vivo in the rat brain has been obtained. In vitro, the autoregulatory vector exhibits an induced expression level superior to that obtained using the constitutive CMV promoter. Although extinction of the transgene after removal of tetracycline was rapid (less than 3 days), inducibility after addition of tetracycline was slow (about 14 days). This kinetics is suitable for therapeutic gene expression in slowly progressive diseases while allowing rapid switch-off in case of undesirable effects. As compared to previously described autoregulatory tet-repressible (tetOFF) AAV vectors, the tet-inducible (tetON) vector prevents chronic antibiotic administration in the uninduced state.

Irradiation of cochlear structures during vestibular schwannoma radiosurgery and associated hearing outcome

OBJECT The purpose of this study was to measure the dose of radiation delivered to the cochlea during a Gamma knife surgery (GKS) procedure for treatment of patients with vestibular schwannomas (VSs), and to analyze the relationship between cochlear irradiation and the hearing outcome of these patients. METHODS Eighty-two patients with VSs were treated with GKS using a marginal dose of 12 Gy. No patient had neurofibromatosis Type 2 disease, and all had a Gardner-Robertson hearing class of I to IV before treatment, and a radiological and audiological follow-up of at least 1-year after GKS. The dosimetric data of the volume of the cochlea were retrospectively analyzed and were correlated with the auditory outcome of patients. RESULTS The mean radiation dose delivered to the cochlear volume ranged from 1.30 to 10.00 Gy (median 4.15 Gy). The cochlea received significantly higher radiation doses in patients with worsening of hearing after GKS. A highly significant association between the cochlear and the intracanalicular dose of radiation delivered during GKS was found. CONCLUSIONS During GKS for VSs, relatively high doses of radiation can be delivered to the cochlea. Worsening of hearing after GKS can be the consequence of either radiation injury to the cochlea or the irradiation dose delivered into the auditory canal, or both.

Sixty-Four-Row Multisection CT Angiography for Detection and Evaluation of Ruptured Intracranial Aneurysms: Interobserver and Intertechnique Reproducibility

BACKGROUND AND PURPOSE: The purpose of this work was to assess intertechnique and interobserver reproducibility of 64-row multisection CT angiography (CTA) used to detect and evaluate intracranial aneurysms. MATERIALS AND METHODS: From October 2005 to November 2006, 54 consecutive patients with nontraumatic subarachnoid hemorrhage (SAH) underwent both CTA and digital substraction angiography (DSA). Four radiologists independently reviewed CT images, and 2 other radiologists reviewed DSA images. Aneurysm diameter (D), neck width (N), and the presence of a branch arising from the sac were assessed. RESULTS: DSA revealed 67 aneurysms in 48 patients and no aneurysm in 6 patients. Mean sensitivity and specificity of CTA for the detection of intracranial aneurysms were, respectively, 94% and 90.2%. For aneurysms less than 3 mm, CTA had a mean sensitivity of 70.4%. Intertechnique and interobserver agreements were good for the detection of aneurysms (mean κ = 0.673 and 0.732, respectively) and for the measurement of their necks (mean κ = 0.753 and 0.779, respectively). Intertechnique and interobserver agreements were excellent for the measurement of aneurysm diameters (mean κ = 0.847 and 0.876, respectively). In addition, CTA was accurate in determining the N/D ratio of aneurysms and adjacent arterial branches. However, the N/D ratio was overestimated by all of the readers at CTA. CONCLUSION: Sixty-four-row multisection CTA is an imaging method with a good interobserver reproducibility and a high sensitivity and specificity for the detection and the morphologic evaluation of ruptured intracranial aneurysms. It may be used as an alternative to DSA as a first-intention imaging technique in patients with SAH.

Apparent Diffusion Coefficient and Cerebral Blood Volume in Brain Gliomas: Relation to Tumor Cell Density and Tumor Microvessel Density Based on Stereotactic Biopsies

BACKGROUND AND PURPOSE: MR imaging–based apparent diffusion coefficient (ADC) and regional cerebral blood volume (rCBV) measurements have been related respectively to both cell and microvessel density in brain tumors. However, because of the high degree of heterogeneity in gliomas, a direct correlation between these MR imaging–based measurements and histopathologic features is required. The purpose of this study was to correlate regionally ADC and rCBV values with both cell and microvessel density in gliomas, by using coregistered MR imaging and stereotactic biopsies. MATERIALS AND METHODS: Eighteen patients (9 men, 9 women; age range, 19–78 years) with gliomas underwent diffusion-weighted and dynamic susceptibility contrast-enhanced MR imaging before biopsy. Eighty-one biopsy samples were obtained and categorized as peritumoral, infiltrated tissue, or bulk tumor, with quantification of cell and microvessel density. ADC and rCBV values were measured at biopsy sites and were normalized to contralateral white matter on corresponding maps coregistered with a 3D MR imaging dataset. ADC and rCBV ratios were compared with quantitative histologic features by using the Spearman correlation test. RESULTS: The highest correlations were found within bulk tumor samples between rCBV and cell density (r=0.57, P < .001) and rCBV and microvessel density (r=0.46, P < .01). An inverse correlation was found between ADC and microvessel density within bulk tumor (r=−0.36, P < .05), whereas no significant correlation was found between ADC and cell density. CONCLUSION: rCBV regionally correlates with both cell and microvessel density within gliomas, whereas no regional correlation was found between ADC and cell density.