Li-Fraumeni syndrome: multiple distinct brain tumours in two brothers.

Li-Fraumeni syndrome is a rare autosomal dominant cancer-prone condition characterized by the occurrence of a large set of different types of cancer in a patient and their family. A germline disease-causing mutation of the gene encoding the p53 protein is associated with the syndrome. We report on a family in which segregation of a TP53 mutation in two generations was associated with two brain tumours, a leiomyosarcoma and a thyroid carcinoma in four male patients. The main patient presented with seizures revealing several primary brain tumours. We review recent views on its molecular basis and discuss management of the condition as well as a review of the literature.

[Intraoperative MRI and epilepsy surgery]. / IRM opératoire et chirurgie de l'épilepsie.

Intraoperative imaging, in particular intraoperative MRI, is a developing area in neurosurgery and its role is currently being evaluated. Its role in epilepsy surgery has not been defined yet and its use has been limited. In our experience with a compact and mobile low-field intraoperative MRI system, a few epilepsy surgeries have been performed using this technique. As the integration of imaging and functional data plays an important role in the planning of epilepsy surgery, intraoperative verification of the surgical result may be highly valuable. Therefore, teams that have access to intraoperative MRI should be encouraged to use this technique prospectively to evaluate its current relevance in epilepsy surgery.

Endovascular treatment of intracranial aneurysms as the first thérapeutic option.

BACKGROUND AND PURPOSE: To prospectively evaluate the results of endovascular treatment (EVT) of intracranial aneurysms when it is considered as first-intention treatment. METHODS: From April 2004-October 2006, 167 consecutive patients with 202 aneurysms were treated in our institution. Five patients with a ruptured aneurysm with an associated haematoma were excluded. In 162 patients with 197 aneurysms, EVT was considered as first-intention treatment. RESULTS: Surgical clipping was performed in 25 aneurysms (25/197=12.7%) including 22 aneurysms excluded from EVT and three EVT failures. EVT was thus attempted in 144 patients with 175 aneurysms and successfully performed in 141 patients with 172 aneurysms (172/197=87.3%). EVT failure rate was 1.7%. Clinical outcome according to the modified Glasgow Outcome Scale was: Excellent, 81.5%; Good, 7%; Poor or Fair, 3.5%; Death, 8%. Procedural complications occurred in 17 cases (10%). Balloon- or stent-assisted techniques were used in 60 cases (34.9%) and were not associated with higher complication rate. Overall procedural morbidity and mortality rates were 4.2 and 2.1%. Initially, complete occlusion was obtained in 68%, neck remnant in 23%, and incomplete occlusion in 9% of aneurysms. Follow-up (mean 11 months) was obtained in 119 aneurysms and showed major recanalisation--that required re-treatment--in 13 cases (11%) and minor recanalisation in 17 cases (14.3%). CONCLUSION: Our findings suggest that new endovascular techniques allow proposing EVT as first-intention treatment in 87.3% of patients with intracranial aneurysms. This therapeutic strategy is associated with good clinical results. However, anatomical results are not improved and remain the EVT limiting factor.

Anatomical and physiological basis, clinical and surgical considerations, mechanisms underlying efficacy and future prospects of cortical stimulation for pain.

The analgesic efficacy of cortical stimulation on refractory neuropathic pain has been established. Although it offers pain relief to 45-75% of the patients, this technique remains under evaluation and the definitive protocol for its application has not been established yet. The mechanisms underlying the analgesic efficacy of cortical stimulation are still largely unknown. Successive technical adaptations have been proposed and tried in order to reduce the number of non-responding patients. In this chapter, we summarize the limited amount of crucial information that has been acquired so far on pain processing in the central nervous system, on the functional pathophysiology of neuropathic pain and on the mechanisms underlying the efficacy of cortical stimulation. We also discuss key issues that could help to increase the success rate and enhance the future prospects of the technique.

[Management of low-grade glioma: a retrospective study concerning 201 patients]. / Prise en charge des gliomes de bas grade: série rétrospective de 201 patients.

BACKGROUND AND PURPOSE: Optimal treatment for low-grade glioma remains controversial. Moreover, though surgery is recommended for disease management, evidence is lacking concerning the appropriate extent of surgery and the use of adjunctive therapy. Available data is basically retrospective, coming from series with substantial limitations. We reviewed our institution's series in order to evaluate the efficiency of surgical management and the influence of the extent of surgical removal for patients with low-grade glioma. METHODS: Data were collected from a series of 201 patients who underwent first-intention therapy for low-grade glioma, the standard practice in our institution between 1994 and 2005. After applying certain exclusion criteria, we retained for analysis 123 patients with grade II glioma (WHO classification). We compared progression-free survival curves for the three surgical treatment groups defined as biopsy, partial removal, or total removal. RESULTS: Statistical evaluation of the progression free survival shows a benefit in total surgery as a first intention treatment. No statistical significance was demonstrated between partial surgery and stereotactic biopsy. CONCLUSION: For patients with low-grade glioma we recommend total surgical removal as first intention management.

[Intramedullary cavernomas: personal series of 24 cases]. / Les cavernomes intramédullaires: série personnelle de 24 cas.

Intramedullary cavernomas are rare, but with routinely use of MRI detection has improved, raising the problem of choosing the adequate management approach: conservative or surgical. Cavernomas are vascular malformations, but, as hemangioblastomas they appear as vascular tumors of the spinal cord. They can be durably asymptomatic. The symptoms are a progressive clinical deterioration or acute spinal dysfunction (tetra or paraplegia) in case of hemorrhage. Cavernomas have a typical aspect with MRI in contrast with intramedullary gliomas. The lesion is often superficial, covered by the pia-mater, visible immediately after opening the dura, the approach is direct; but in few cases the cavernoma is deep seated in the spinal cord and not visible, the approach is through the midline. It is recommended to perform a complete "en bloc" resection. A yearly MRI control is necessary to search possible "de novo" cases.

Overexpression of mouse IsK protein fused to green fluorescent protein induces apoptosis of human astroglioma cells.

Intracellular K(+) plays an important role in controlling ion homeostasis for maintaining cell volume and inhibiting activity of pro-apoptotic enzymes. Cytoplasmic K(+) concentration is regulated by K(+) uptake via Na(+) -K(+) -ATPase and K(+) efflux through K(+) channels in the plasma membrane. The IsK (KCNE1) protein is known to co-assemble with KCNQ1 (KvLQT1) protein to form a K(+) channel underlying the slowly activating delayed rectifier K(+) outward current which delays voltage activation. In order to further study the activity and cellular localization of IsK protein, we constructed a C-terminal fusion of IsK with EGFP (enhanced green fluorescent protein). Expression of the fusion protein appeared as clusters located in the plasma membrane and induced degeneration of both transiently or stably transfected cells.

Controlled delivery of glial cell line-derived neurotrophic factor by a single tetracycline-inducible AAV vector.

An autoregulated tetracycline-inducible recombinant adeno-associated viral vector (rAAV-pTet(bidi)ON) utilizing the rtTAM2 reverse tetracycline transactivator (rAAV-rtTAM2) was used to conditionally express the human GDNF cDNA. Doxycycline, a tetracycline analog, induced a time- and dose-dependent release of GDNF in vitro in human glioma cells infected with rAAV-rtTAM2 serotype 2 virus. Introducing the Woodchuck hepatitis virus posttranscriptional regulatory element (WPRE) downstream to the rtTAM2 coding sequence, resulted in a more rapid induction and a higher basal expression level. In vivo, 8 weeks after a single injection of the rAAV-rtTAM2-GDNF vector encapsidated into AAV serotype 1 capsids in the rat striatum, the GDNF protein level was 60 pg/mg tissue in doxycycline-treated animals whereas in untreated animals, it was undistinguishable from the endogenous level ( approximately 4 pg/mg tissue). However, a residual GDNF expression in the uninduced animals was evidenced by a sensitive immunohistochemical staining. As compared to rAAV1-rtTAM2-GDNF, the rAAV1-rtTAM2-WPRE-GDNF vector expressed a similar concentration of GDNF in the induced state (with doxycycline) but a basal level (without doxycycline) approximately 2.5-fold higher than the endogenous striatal level. As a proof for biological activity, for both vectors, downregulation of tyrosine hydroxylase was evidenced in dopaminergic terminals of doxycycline-treated but not untreated animals. In conclusion, the rAAV1-rtTAM2 vector which expressed biologically relevant doses of GDNF in the striatum in response to doxycycline with a basal level undistinguishable from the endogenous striatal level, as measured by quantitative ELISA assay, constitutes an interesting tool for local conditional transgenesis.

[A brief history and a few remarks about classifications of aneurysmal subarachnoid hemorrhages and scales of follow-up]. / Petite histoire et quelques réflexions à propos des échelles de grades des hémorragies sous-arachnoïdiennes d'origine anévrismale et des échelles de suivi.

A brief history of the most current scales of aneurysmal subarachnoid hemorrhage and follow-up is presented. Advantages and inaccuracies of these scales are discussed. The World Federation of Neurological Surgeons (WFNS) classification is recommended as the most objective and reliable although some critics exist about its use in particular conditions. The grading of the follow-up is also analyzed. Here, the Glasgow Outcome Scale (GOS) is the most common employed and promoted in a first approach in spite of its briefness. Secondary functional and neuropsychological examination at 6 or 12 months is to be recommended to enable a more accurate evaluation. In conclusion, the WFNS scales for subarachnoid hemorrhage and follow-up is proposed as the best way to allow comparison between work of different centers.

Cystic extramedullary ependymoma.

Intradural extramedullary location of ependymoma is rare. To the best of our knowledge, only 9 cases have been described in the literature. We report a case of a histologically confirmed ependymoma (WHO grade II) presented in the MR imaging as a cystic, nonenhancing thoracic intradural extramedullary lesion compressing the spinal cord. The cystic appearance mimicking an arachnoid cyst at diagnosis and the leptomeningeal dissemination developed later were peculiarities that have never been previously described in relation to these rare tumors.

Endovascular treatment of intracranial aneurysms with a branch arising from the sac.

BACKGROUND AND PURPOSE: The endovascular treatment (EVT) of intracranial aneurysms is no more limited by the presence of a branch at the neck or by the neck width. Saccular aneurysms with a branch arising from the sac, however, are mostly candidates for surgery rather than embolization. We prospectively evaluated the feasibility and safety of the EVT in such cases. METHODS: Between May and November 2004, 9 consecutive patients with a saccular aneurysm that presents a branch arising from the sac were treated by embolization. There were 7 women and 2 men (mean age, 58 years). Six patients presented with a subarachnoid hemorrhage (SAH), and 3 were asymptomatic. All patients were treated by selective coiling with (n = 6) or without (n = 3) the remodeling technique. Clinical outcome was assessed with a modified Glasgow Outcome Scale at 3 months. RESULTS: EVT was successfully performed in all patients and resulted in 7 excellent outcomes and 2 deaths related to SAH complications. The arterial branch could be preserved in 7 cases and intentionally occluded in 2. Neither embolic nor ischemic complication occurred in the vascular territory of the involved branch. Angiographic results showed 5 neck remnants, 2 incomplete occlusions, and 2 complete occlusions. No rebleeding occurred. CONCLUSION: Our study, though limited by its small patient population, suggests that saccular intracranial aneurysms with a branch arising from the sac may be treated by endovascular approach with excellent clinical results; however, larger series with long-term follow-up are mandatory to confirm these preliminary results mostly in terms of anatomic stability.

Co-expression/co-location of S100 proteins (S100B, S100A1 and S100A2) and protein kinase C (PKC-beta, -eta and -zeta) in a rat model of cerebral basilar artery vasospasm.

OBJECT: The cellular events leading to cerebral vasospasm after subarachnoid haemorrhages (SAH) involve a number of members of the protein kinase C (PKC) family. However, whereas calcium is thought to play a number of major roles in the pathophysiology of SAH, a number of PKCs function independently of calcium. We recently emphasized the potential role of the calcium-binding S100 proteins in a 'double haemorrhage' rat model of SAH-induced vasospasm. A number of S100 proteins are known to interfere directly with PKC, or indirectly with PKC substrates. We therefore investigated whether specific S100 proteins and PKCs are co-expressed/co-located in a rat model of SAH-induced vasospasm. METHODS AND RESULTS: SAH-induced vasospasm in rats (by means of a double cisternal injection of autologous blood from a rat femoral artery) distinctly modified the expression levels of calcium-dependent PKC-alpha and PKC-beta and calcium-independent PKC-eta and PKC-zeta in endothelial and smooth-muscle cells. The RNA levels of these four PKC isotypes were determined by quantitative RT-PCR. The present study reveals that, in endothelial cells, the S100B expression/location correlate well with those of PKC-eta, and those of S100A1 with PKC-beta. In smooth-muscle cells S100A2 expression/location correlate with those of PKC-eta, and those of S100B with PKC-zeta. CONCLUSION: The present data argue in favour of a joint action of the S100 protein network and the PKC signalling pathway during cerebral vasospasm.

[Transsphenoidal approach with low field MRI for pituitary adenoma]. / Apport de la résonance magnétique per-opératoire à bas champs dans la chirurgie de l'adénome hypophysaire.

INTRODUCTION: Appropriate evaluation of resection remains one of the major difficulties of surgical treatment of pituitary adenoma. The transsphenoidal approach does not allow direct visual control. Endoscopy provides useful information but may no distinguish well residual adenoma from the pituitary gland. Intraoperative MRI offers new perspectives for assessing the quality of resection. We report our experience with low field intraoperative MRI in surgical treatment of pituitary adenoma. POPULATION: Intraoperative MRI (Polestar N10, 30 patients and Polestar N20, 17 patients) was performed in 45 consecutive patients undergoing surgery for pituitary adenoma. Thirty-seven patients had a macroadenoma. Patients were in the prone position with the head fixed with a three-pin MRI-compatible headholder. METHOD: Coronal T1 MRI scans with enhancement were acquired pre and per operatively. We compared scans and surgical filling (complete removal). If there was a difference, a surgical control was undertaken. RESULTS: Intraoperative images were unavailable for two patients due to small size of the neck and the pituitary glands which were not in the middle in the field of view. For the others, the pituitary glands were in the field of view and the intraoperative scans could be used for comparison. For four patients, there was a discrepancy between surgeon filling and the intraoperative MRI. A control showed no residual adenoma but hemostatic tissue. CONCLUSION: Low field intraoperative MRI is an excellent technique for controlling the size of pituitary adenoma resection.

[Contribution of PET to the management of patients with low-grade glioma]. / Apport de la tomographie à émission de positons dans la prise en charge des gliomes de bas grade.

BACKGROUND AND PURPOSE: Management of patients with low-grade glioma is a major challenge for the neurosurgeon. When is neurosurgery indicated? Should chemotherapy or radiotherapy be used? Many questions without an answer. We reviewed our experience with 65 patients treated for low-grade glioma who had preoperative PET images (FDG or/and MET). We examined the prognostic value of PET and also determined the sensitivity and the specificity of PET images to predict outcome. METHODS: Sixty-five patients with a FDG or MET PET images were analyzed. We used two visual scales and had complete follow-up data for 63 patients. The free interval was the principal criterion for statistical analysis. The sensitivity and the specificity of PET images was determined. RESULTS: Strong FDG uptake was correlated with a short free interval (p=0.001). Similar results were found with the MET analysis (p=0.0076). We had a PET with MET and FDG for 36 patients. The sensitivity was 66% and the specificity 94% for FDG PET. Sensitivity was 100% and specificity 53% for MET PET. CONCLUSIONS: PET imaging provides a prognostic factor independent from histology. MET PET is the best exam for the follow-up of patients with low-grade glioma and is helpful for separating aggressive from low-grade glioma.

Efficient early and sustained transduction of human fetal mesencephalon using adeno-associated virus type 2 vectors.

The success of transplantation of human fetal mesencephalic tissue into the putamen of patients with Parkinson's disease (PD) is still limited by the poor survival of the graft. In animal models of fetal transplantation for PD, antiapoptotic agents, such as growth factors or caspase inhibitors, or agents counteracting oxidative stress enhance the survival and reinnervation potential of the graft. Genetic modification of the transplant could allow a local and continuous delivery of these factors at physiologically relevant doses. The major challenge remains the development of strategies to achieve both early and sustained gene delivery in the absence of vector-mediated toxicity. We recently reported that E14 rat fetal mesencephalon could be efficiently tranduced by adeno-associated virus type 2 (AAV2) vectors and that gene expression was maintained until at least 3 months after transplantation in the adult rat striatum. Here we report that an AAV2 vector can mediate the expression of the EGFP reporter gene under the control of a CMV promoter in organotypic cultures of freshly explanted solid fragments of human fetal mesencephalic tissue as early as 3 days to at least 6 weeks postinfection. These results suggest that AAV2 vectors could be used to genetically modify the human fetal tissue prior to transplantation to Parkinson's patients to promote graft survival and integration.

S100A5: a marker of recurrence in WHO grade I meningiomas.

Some WHO grade I intracranial meningiomas resected from the same sites and with the same quality of resection (Simpson's grading scale) recur, while others do not. The reasons for this variability in occurrence of recurrence have not yet been determined. We therefore investigated the prognostic recurrence value of seven biological markers on a series of completely resected WHO grade I meningiomas. For this purpose, we analysed a series of 33 WHO grade I meningiomas totally resected between 1980 and 1990 (a follow-up of 10 years), including 14 cases of recurrence. The fixed tumour material from each meningioma was submitted to histochemical analyses targeting galectin-3 and its binding sites, the S100A5, S100A6 and S100B proteins, and cathepsin-B and -D. The levels of expression were assessed semi-quantitatively (in terms of the staining intensity and the labelling index) and submitted to uni- and multivariate analyses. Of all the markers investigated, only S100A5 expression can be associated with any significant prognostic value in the matter of recurrence. More particularly, the meningiomas with high levels of S100A5 staining intensity either did not recur, or recurred later than those with a low immunopositive S100A5 intensity (P = 0.004). Cox regression analyses demonstrated that this latter marker was associated with significant prognostic values independent of the patients' ages. Furthermore, the combination of the patients' ages and S100A5 staining intensity permitted the identification of a group with a particularly high risk of recurrence, that is, the patients younger than 55 and with meningiomas exhibiting low S100A5 intensities (P = 0.001). In conclusion, the S100A5 protein could play a role in the recurrence of totally resected WHO grade I meningiomas.

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 beta-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. No inflammatory response has been described following rAAV2 administration to the brain. In contrast, antibodies to AAV2 capsid and transgene product were elicited but no reduction of transgene expression was observed and readministration of vector without loss of efficiency was possible from 3 months after the first injection. Based on the success of pioneer work performed with marker genes, various strategies for therapeutic gene delivery were designed. These include enzyme replacement in lysosomal storage diseases, Canavan disease and Parkinson's disease; delivery of neuroprotective factors in Parkinson's disease, Huntington disease, Alzheimer's disease, amyotrophic lateral sclerosis, ischemia and spinal cord injury; as well as modulation of neurotransmission in epilepsy and Parkinson's disease. Several of these strategies have demonstrated promising results in relevant animal models. However, their implementation in the clinics will probably require a tight regulation and a specific targeting of therapeutic gene expression which still demands further developments of the vectors.

[Surgical treatment of intramedullary tumors. Experience with 316 cases]. / Le traitement chirurgical des tumeurs intramédullaires. Expérience de 316 cas.

We report our experience on the surgical treatment of 316 intraspinal cord tumors at the time we presented our lecture to the Academy. Our series is based on 124 ependymomas, 76 astrocytomas, 30 hemangioblastomas and 21 cavernomas to focus on the most frequent tumors. Ependymomas were totally removed in 90%, astrocytomas in 40% and hemangioblastomas so as cavernomas in 100% of the cases. We describe our surgical technique so as our results. We confirm that the surgical risks are directly related to the preoperative neurological situation. Handicapped patients are subject to high surgical risks. Complete removal is the aim since surgery is the gold standard treatment. Good quality of life may be expected in most of the patients (approximately 90%) operated with moderate neurological deficit before surgery.

Cathepsin B, D and K expression in adamantinomatous craniopharyngiomas relates to their levels of differentiation as determined by the patterns of retinoic acid receptor expression.

AIMS: To investigate the potential predictive value of cathepsins B, D and K in a series of 51 adamantinomatous craniopharyngiomas. While almost always benign, craniopharyngiomas exhibit a high propensity to recur postsurgically and biological markers are therefore needed to predict their recurrence. We have previously demonstrated the potential predictive value of retinoic acid receptors (RARs) (Lefranc et al., J. Neurosurg. 2003; 98; 145-153). METHODS AND RESULTS: Computer-assisted microscopy was used to determine quantitatively the immunohistochemical levels of expression of the alpha, beta and gamma RAR subtypes and cathepsins B, D and K. The levels of expression of cathepsin D and of cathepsin B correlated significantly with the levels of expression of RARbeta. The levels of expression of cathepsin K correlated significantly with the levels of expression of RARgamma. CONCLUSIONS: Recurrent adamantinomatous craniopharyngiomas are characterized by low levels of RARbeta and high levels of RARgamma. The tendency to recurrence seems, at least partly, to relate to the fact that (i) craniopharyngiomas with low levels of RARbeta express low levels of cathepsin D, and (ii) craniopharyngiomas with high levels of RARgamma express high levels of cathepsin K.