Predictive Factors of Surgical Outcome in Frontal Lobe Epilepsy Explored with Stereoelectroencephalography.

BACKGROUND: Resective surgery established treatment for pharmacoresistant frontal lobe epilepsy (FLE), but seizure outcome and prognostic indicators are poorly characterized and vary between studies. OBJECTIVE: To study long-term seizure outcome and identify prognostic factors. METHODS: We retrospectively analyzed 42 FLE patients having undergone surgical resection, mostly preceded by invasive recordings with stereoelectroencephalography (SEEG). Postsurgical outcome up to 10-yr follow-up and prognostic indicators were analyzed using Kaplan-Meier analysis and multivariate and conditional inference procedures. RESULTS: At the time of last follow-up, 57.1% of patients were seizure-free. The estimated chance of seizure freedom was 67% (95% confidence interval [CI]: 54-83) at 6 mo, 59% (95% CI: 46-76) at 1 yr, 53% (95% CI: 40-71) at 2 yr, and 46% (95% CI: 32-66) at 5 yr. Most relapses (83%) occurred within the first 12 mo. Multivariate analysis showed that completeness of resection of the epileptogenic zone (EZ) as defined by SEEG was the main predictor of seizure outcome. According to conditional inference trees, in patients with complete resection of the EZ, focal cortical dysplasia as etiology and focal EZ were positive prognostic indicators. No difference in outcome was found in patients with positive vs negative magnetic resonance imaging. CONCLUSION: Surgical resection in drug-resistant FLE can be a successful therapeutic approach, even in the absence of neuroradiologically visible lesions. SEEG may be highly useful in both nonlesional and lesional FLE cases, because complete resection of the EZ as defined by SEEG is associated with better prognosis.

Local and remote epileptogenicity in focal cortical dysplasias and neurodevelopmental tumours.

During the pre-surgical evaluation of drug-resistant epilepsy, the assessment of the extent of the epileptogenic zone and its organization is a crucial objective. Indeed, the epileptogenic zone may be organized as a simple focal lesional site or as a more complex network (often referred to as the 'epileptogenic network') extending beyond the lesion. This distinction is particularly relevant in developmental lesions such as focal cortical dysplasias or dysembryoplastic neuroepithelial tumours and may determine both the surgical strategy and the prognosis. In this study, we have quantified the epileptogenic characteristic of brain structures explored by depth electrodes in 36 patients investigated by stereoelectroencephalography and suffering from focal drug-resistant epilepsy associated with focal cortical dysplasias or dysembryoplastic neuroepithelial tumours. This quantification was performed using the 'Epileptogenicity Index' method that accounts for both the propensity of a brain area to generate rapid discharges and the time for this area to get involved in the seizure. Epileptogenicity Index values range from 0 (no epileptogenicity) to 1 (maximal epileptogenicity). We determined Epileptogenicity Index from signals recorded in distinct brain structures including the lesional site. We studied the type of epileptogenic zone organization (focal versus network) and looked for a correlation with clinical data and post-surgical outcome. Mean Epileptogenicity Index in lesional regions was 0.87 (+/-0.25), and 0.29 (+/-0.30) in 'non-lesional' structures. The number of highly epileptogenic structures (defined by Epileptogenicity Index value >or=0.4) was 3.14 (+/-1.87) in the whole population. We found that 31% of patients had only one epileptogenic structure (N(EI>or=0.4) = 1), therefore disclosing a strictly focal epileptogenic zone organization while 25 patients had more than one epileptogenic region, disclosing a network (61%) or bilateral (8%) epileptogenic zone organization. We observed a trend for a difference in seizure outcome according to the type of epileptogenic zone organization. Indeed, 57% of patients with network organization and 87% with focal organization were seizure-free while none of those with bilateral organization became seizure-free. The determination of Epileptogenicity Index computed from electrophysiological signals recorded according to the stereoelectroencephalography technique is a novel tool. Results suggest that it can help in the delineation of the epileptogenic zone associated with brain lesions and that it could be used in the definition of the subsequent surgical resection.

Stereoelectroencephalography in presurgical assessment of MRI-negative epilepsy.

According to most existing literature, the absence of an MRI lesion is generally associated with poorer prognosis in resective epilepsy surgery. Delineation of the epileptogenic zone (EZ) by intracranial recording is usually required but is perceived to be more difficult in 'MRI negative' cases. Most previous studies have used subdural recording and there is relatively less published data on stereoelectroencephalography (SEEG). The objective of this study was to report the experience of our group in using SEEG in presurgical evaluation, comparing its effectiveness in normal and lesional MRI cases. One hundred consecutive patients undergoing SEEG for presurgical assessment were studied. Forty-three patients out of one hundred (43%) had normal MRI and 57 (57%) had lesional MRI. Successful localization was achieved with no difference between these two groups, in 41/43 (95%) normal MRI and in 55/57 (96%) lesional MRI cases (P = 1.00). Surgery was proposed in 84/100 patients and contraindicated in 16/100 with no significant difference between lesional and MRI-negative groups (P > 0.05). At 1 year follow-up, 11/20 (55%) of those having undergone cortectomy in the MRI-negative group and 21/40 (53%) in the lesional MRI group were entirely seizure free (P > 0.05) and these proportions were maintained at 2 years follow-up. Significant improvement in seizure control (ILAE outcome groups 1-4) was achieved in >90% cases with no difference between groups (P > 0.05). Of MRI-negative cases that underwent surgery, 10/23 (43%) had focal cortical dysplasia. This series showed that SEEG was equally effective in the presurgical evaluation of MRI-negative and lesional epilepsies.

Differential dynamic of action on cortical and subcortical structures of anesthetic agents during induction of anesthesia.

BACKGROUND: Dynamic action of anesthetic agents was compared at cortical and subcortical levels during induction of anesthesia. Unconsciousness involved the cortical brain but suppression of movement in response to noxious stimuli was mediated through subcortical structures. METHODS: Twenty-five patients with Parkinson disease, previously implanted with a deep-brain stimulation electrode, were enrolled during the implantation of the definitive pulse generator. During induction of anesthesia with propofol (n = 13) or sevoflurane (n = 12) alone, cortical (EEG) and subcortical (ESCoG) electrogenesis were obtained, respectively, from a frontal montage (F3-C3) and through the deep-brain electrode (p0-p3). In EEG and ESCoG spectral analysis, spectral edge (90%) frequency, median power frequency, and nonlinear analysis dimensional activation calculations were determined. RESULTS: Sevoflurane and propofol decreased EEG and ESCoG activity in a dose-related fashion. EEG values decreased dramatically at loss of consciousness, whereas there was little change in ESCoG values. Quantitative parameters derived from EEG but not from ESCoG were able to predict consciousness versus unconsciousness. Conversely, quantitative parameters derived from ESCoG but not from EEG were able to predict movement in response to laryngoscopy. CONCLUSION: These data suggest that in humans, unconsciousness mainly involves the cortical brain, but that suppression of movement in response to noxious stimuli is mediated through the effect of anesthetic agents on subcortical structures.

Effects of chronic subthalamic stimulation on nonmotor fluctuations in Parkinson's disease.

The aim of this study was to assess the outcome of nonmotor fluctuations (NMF) after chronic Subthalamic nucleus (STN) Deep Brain Stimulation (DBS) in Parkinson's disease(PD). Chronic stimulation of the STN has proved to be an effective treatment for advanced PD with motor complications. The outcome of NMF, which are also disabling, remains unknown. Forty-patients underwent bilateral STN stimulation. Each patient was interviewed before and after 1 yr of STN DBS with a structured questionnaire about their NMF. After 1 yr of chronic stimulation, the improvement in the motor score (UPDRS III) and dyskinesia amounted respectively to 67.4 and 76.3%. The decrease in motor fluctuations (MF) was 59% and 13 patients reported that their MF had disappeared. Comparatively, a reduction of the total number of NMF was also observed (mean number preoperatively: 15.6 per patient, postoperatively: 6.6). Most of the nonmotor fluctuating symptoms occurred in the "off" state preoperatively and no longer depended on the patient's motor state after surgery. The improvement in NMF was not identical for the different categories: pain/sensory fluctuations showed the best response to STN DBS (84.2%). Dysautonomic and cognitive fluctuations were also markedly improved (>60%) while psychic fluctuations remained the most frequent postoperative NMF observed. Some incapacitating manifestations such as drenching sweats and akathisia showed a remarkably good response to STN stimulation. In conclusion STN DBS alleviates NMF. It has strikingly successful effects on sensory, dysautonomic and cognitive fluctuations. However, psychic fluctuations respond less consistently to this treatment.

Bilateral deep brain stimulation of the globus pallidus to treat tardive dyskinesia.

CONTEXT: Tardive dyskinesia (TD) is a common and potentially disabling disorder induced by use of antipsychotic drugs for which medical treatment often gives disappointing results. OBJECTIVE: To assess the efficacy of bilateral deep brain stimulation of the internal part of the globus pallidus to treat severe TD. DESIGN: Prospective phase 2 multicenter study. SETTING: Six French university hospitals. Patients Patients with severe TD refractory to medical treatment were studied to evaluate the severity of abnormal involuntary movements before and after 6 months of bilateral globus pallidus deep brain stimulation. A 2-step open Fleming procedure was used to avoid unnecessary accrual of patients. A successful outcome was defined as a decrease of more than 40% in the main outcome measure at 6 months. The early stopping rule was invoked if the number of successful outcomes in 10 patients was fewer than 2, or 5 or more. A double-blind evaluation in the presence and absence of stimulation was performed at 6 months after surgery. Main Outcome Measure Change in score on the Extrapyramidal Symptoms Rating Scale. RESULTS: At 6 months after surgery, the Extrapyramidal Symptoms Rating Scale score had decreased compared with baseline by more than 40% (mean improvement, 61%; range, 44%-75%) in the first 10 patients included. In accord with the 2-step open Fleming procedure, we ended the trial at the first step and concluded that pallidal stimulation is an effective treatment for TD. The efficacy of the treatment was confirmed by a double-blind evaluation, with a mean decrease of 50% (range, 30%-66%) (P = .002) in the Extrapyramidal Symptoms Rating Scale score when stimulation was applied compared with the absence of stimulation. There were no marked changes in the patients' psychiatric status. CONCLUSION: Although these results need to be confirmed in a larger group of patients with a longer follow-up, bilateral globus pallidus deep brain stimulation seems to offer a much-needed new treatment option for disabling TD.

Large-scale expression study of human mesial temporal lobe epilepsy: evidence for dysregulation of the neurotransmission and complement systems in the entorhinal cortex.

Human mesial temporal lobe epilepsies (MTLE) are the most frequent form of partial epilepsies and display frequent pharmacoresistance. The molecular alterations underlying human MTLE remain poorly understood. A two-step transcriptional analysis consisting in cDNA microarray experiments followed by quantitative RT-PCR validations was performed. Because the entorhinal cortex (EC) plays an important role in the pathophysiology of the MTLE and usually discloses no detectable or little cell loss, resected EC and each corresponding lateral temporal neocortex (LTC) of MTLE patients were used as the source of disease-associated and control RNAs, respectively. Six genes encoding (i) a serotonin receptor (HTR2A) and a neuropeptide Y receptor type 1 (NPY1R), (ii) a protein (FHL2) associating with the KCNE1 (minK) potassium channel subunit and with presenilin-2 and (iii) three immune system-related proteins (C3, HLA-DR-gamma and CD99), were found consistently downregulated or upregulated in the EC of MTLE patients as compared with non-epileptic autopsy controls. Quantitative western blot analyses confirmed decreased expression of NPY1R in all eight MTLE patients tested. Immunohistochemistry experiments revealed the existence of a perivascular infiltration of C3 positive leucocytes and/or detected membrane attack complexes on a subset of neurons, within the EC of nine out of eleven MTLE patients. To summarize, a large-scale microarray expression study on the EC of MTLE patients led to the identification of six candidate genes for human MTLE pathophysiology. Altered expression of NPY1R and C3 was also demonstrated at the protein level. Overall, our data indicate that local dysregulation of the neurotransmission and complement systems in the EC is a frequent event in human MTLE.

Brainstem metastases: management using gamma knife radiosurgery.

OBJECTIVE: Brainstem metastasis is an uncommon complication of systemic cancer, generally considered to have a highly unfavorable prognosis. Surgical risks are high and standard radiation or chemotherapy have little effect. The purpose of this study is to evaluate our experience using Gamma Knife radiosurgery (GKRS) for the management of brainstem metastasis. METHODS: Between July 1992 and March 2001, we treated 28 patients with brainstem metastasis using GKRS. Lesions were located in the pons in 17 patients, midbrain in nine, and medulla oblongata in two. At time of the radiosurgery, eight patients presented with another supratentorial metastasis. The most frequent primary tumor site was the lung (13 cases) followed by the melanoma in four cases, the kidney in two, and other locations in six. Only six patients underwent fractionated whole-brain radiation therapy. Mean marginal radiation dose for GKRS was 19.6 Gy (range, 11-30). Mean maximum diameter was 17.2 mm (range, 10-30). RESULTS: No GKRS-related morbidity was observed. Local tumor control was achieved in 92% of patients. Twenty-six patients have died. Death was related to the progression of the brainstem lesion in two cases. Mean and median survival after GKRS were 10.2 and 12 months, respectively. Follow-up periods in the two surviving patients were 12 and 13 months. CONCLUSION: The results of this small series demonstrate that GKRS can be a valuable modality for safe and effective management of brain stem metastasis. Owing to the high risk of surgical resection and low efficacy of medical treatment, radiosurgery can be proposed upfront.

Addiction in Parkinson's disease: impact of subthalamic nucleus deep brain stimulation.

In Parkinson's disease, dopamine dysregulation syndrome (DDS) is characterized by severe dopamine addiction and behavioral disorders such as manic psychosis, hypersexuality, pathological gambling, and mood swings. Here, we describe the case of 2 young parkinsonian patients suffering from disabling motor fluctuations and dyskinesia associated with severe DDS. In addition to alleviating the motor disability in both patients, subthalamic nucleus (STN) deep brain stimulation greatly reduced the behavioral disorders as well as completely abolished the addiction to dopaminergic treatment. Dopaminergic addiction in patients with Parkinson's disease, therefore, does not constitute an obstacle to high-frequency STN stimulation, and this treatment may even cure the addiction.

Phase II study of temozolomide without radiotherapy in newly diagnosed glioblastoma multiforme in an elderly populations.

BACKGROUND: Currently, the survival of patients age > 70 years with glioblastoma multiforme (GBM) ranges from 4 months to 6 months, although radiotherapy and/or chemotherapy may prolong survival in certain subgroups. Temozolomide is an oral chemotherapeutic agent with efficacy against malignant gliomas and a favorable safety profile. This open-label, single-center, Phase II study was designed to evaluate the efficacy and safety of temozolomide as first-line chemotherapy and exclusive treatment in elderly patients with newly diagnosed GBM. METHODS: Chemotherapy-naïve patients (age > 70 years) were treated with temozolomide at a dose of 150-200 mg/m(2) per day for 5 consecutive days of a 28-day cycle until they developed disease progression. No radiation therapy was administered. The primary endpoint was median overall survival (OS); secondary endpoints included progression-free survival (PFS) and toxicity. RESULTS: Thirty-two patients (median age, 75 years; median Karnofsky performance status, 70) experienced a median OS of 6.4 months and a median PFS of 5.0 months. Of 29 patients who were assessed for response, 9 patients (31%) achieved a partial response, 12 patients (41%) maintained stable disease, and 8 patients (28%) developed progressive disease. Adverse events primarily were mild, with NCI CTC Grade 3-4 thrombocytopenia and neutropenia reported to occur in 6% and 9% of patients, respectively. No neurotoxicity was observed. Treatment delays and dose reductions occurred in 13% and 14% of cycles, respectively. CONCLUSIONS: Temozolomide represents a safe, easily administered, and effective therapeutic approach for elderly patients with newly diagnosed GBM.

Intrathecal morphine infusion for chronic non-malignant pain: a multiple center retrospective survey.

Intrathecal morphine (ITM) is commonly used for the treatment of cancer pain. There is reluctance for its use in France to treat chronic noncancer pain. In order to appreciate its popularity, efficacy, dose escalation with time, and long-term tolerance, we carried out a retrospective study in the neurosurgery departments of university teaching hospitals in France involved in intrathecal drug therapy. Only 44 patients with chronic noncancer pain used implanted pumps for ITM treatment. Nineteen patients were available for detailed analysis. This survey concerns these 19 patients. There were 13 women and six men. Their average age was 48.8 years (range: 30-69 y). The mean duration of pain before pump implantation was 100 months (range: 12-240 m). The mean follow-up since implantation was 54 m (range: 4-144 m). Thirteen patients were suffering from postsurgery lumbar and radicular pain. The average initial and final dose per day of morphine was 1.3 mg (range: 1-2 mg) and 2.5 mg (range: 1-6.7 mg) for patients with nociceptive pain and 1.2 mg (range: 0.7-2 mg) and 3 mg (range: 1-10 mg) for patients with mixed pain, respectively. Five (26.3%) of 19 patients returned to their initial jobs. Increase in activity level was reported as good in seven patients (36.8%). Patient satisfaction rate was 90%. The VAS rate was reduced to 49.2% of the initial values while the subjective pain relief was estimated at 67.8%. Two cases (10.5%) of late pump site infection and two patients (10.5%) with catheter displacements were recorded. Side effects imputable to morphine included; constipation, somnolence, decreased libido, weight gain, amenorrhoea, vomiting, nightmares, and itching. No development of tolerance or addiction were recorded. We conclude that in well selected cases ITM should be considered as a possible therapeutic option in the treatment of intractable chronic benign pain.

Supraspinal antinociceptive effects of mu and delta agonists involve modulation of adenosine uptake.

BACKGROUND: The modulation of extracellular adenosine concentration by opioids provides evidence that the antinociceptive effects of these compounds involve endogenous adenosine. The aim of this study was to determine whether there is a relation between the inhibition of brain synaptosome adenosine uptake by opioid agonists and the analgesic effects of these compounds. METHODS: The authors used the hot plate and tail-pinch tests to evaluate in mice (C57BL/6 females; weight, 25-30 g) the effects of caffeine, a nonspecific adenosine receptor antagonist, on the antinociceptive effect induced by the intracerebroventricular administration of oxymorphone as a mu agonist, SNC80 as a delta agonist, or U69593 as a kappa agonist. They also investigated the effect of these opioid receptor agonists on the uptake of adenosine by whole brain synaptosomes. RESULTS: Caffeine decreased the analgesic effects induced by oxymorphone or SNC80 but not those induced by U69593. Oxymorphone and SNC80 inhibited adenosine uptake by brain cells, but U69593 did not. CONCLUSION: The antinociceptive effects obtained with mu or delta (but not kappa) agonists administered supraspinally were indicative of the involvement of modulation of adenosine uptake.

[Pathology of myxoid bone tumors of the skull base]. / Tumeurs osseuses myxoïdes de la base du crâne: à propos de 9 cas.

Myxoid bone tumors of the skull encompass chordomas and chondrosarcomas. Their accurate diagnosis is usually a challenge and it is of utmost importance to identify chordomas because of the poorer prognosis. Even if the topography of the tumor is suggestive (median versus lateral), modern imaging is not specific enough and the diagnosis is based on histological features. We report nine cases of myxoid bone tumors of the skull including four chordomas, one chondroid chordoma and four chondrosarcomas. Smears are useful for rapid intraoperative diagnosis. Chondrosarcomas show cords of small round cells in a myxoid background while chordomas are made of multilayered sheets of larger, often vacuolated cells. Histology shows areas of cartilaginous matrix associated with myxoid areas in chondrosarcomas and in chondroid chordomas. Immunohistochemistry is determinant showing the expression of epithelial markers and Tau protein in chordomas only.

Functional outcome after gamma knife surgery or microsurgery for vestibular schwannomas.

OBJECT: Microsurgical excision is an established treatment for vestibular schwannoma (VS). In 1992 the authors used a patient questionnaire to evaluate the functional outcome and quality of life in a series of 224 consecutive patients. In addition, starting with gamma knife surgery (GKS) in 1992, the authors decided to use the same methodology to evaluate prospectively the results of this modality to compare the two alternatives. METHODS: Among the 500 patients who were included prospectively, the authors only evaluated patients in whom GKS was the primary treatment for unilateral VS. Four years of follow up was available for the first 104 consecutive patients. Statistical analysis of the GKS and microsurgery populations has shown that only a comparison of Stage II and III (according to the Koos classification) was meaningful in terms of group size and preoperative risk factor distribution. Objective results and questionnaire answers from the first 97 consecutive patients were compared with the 110 patients in the microsurgery group who fulfilled the inclusion criteria. Questionnaire answers indicated that 100% of patients who underwent GKS compared with 63% of patients who underwent microsurgery had no new facial motor disturbance. Forty-nine percent of patients who underwent GKS (17% in the microsurgery study) had no ocular symptoms, and 91% of patients treated with GKS (61% in the microsurgery study) had no functional deterioration after treatment. The mean hospitalization stay was 3 days after GKS and 23 days after microsurgery. All the patients who underwent GKS who had been employed, except one, had kept the same professional activity (56% in the microsurgery study). The mean time away from work was 7 days for GKS (130 days in the microsurgery study). Among patients whose preoperative hearing level was Class 1 according to the Gardner and Robertson scale, 70% preserved functional hearing after GKS (Class 1 or 2) compared with only 37.5% in the microsurgery group. CONCLUSIONS: Functional side effects happen during the first 2 years after radiosurgery. Findings after 4 years of follow up indicated that GKS provided better functional outcomes than microsurgery in this patient series.

[Contribution of magnetic resonance spectrometry to the diagnosis of intracranial tumors]. / Apports de la spectrométrie par résonance magnétique dans le diagnostic de nature des processus occupants intracrâniens.

Magnetic resonance spectroscopy (MRS) is a method enabling the analysis of the tissue metabolic content. It may offer a more accurate diagnosis of the intracranial tumors than conventional MRI sequences. MRS of normal brain parenchyma displays 4 main metabolites: N-acetyl aspartate (neuronal marker), creatine (cellular density marker), choline (membrane activity marker) and myoinositol (glial marker); pathological processes lead to variations of the level of these metabolites and/or the appearance of abnormal metabolites (lactate), following different patterns according to pathological process involved: glioma, meningioma, metastasis, bacterial or toxoplasmic abscess, radionecrosis. The potential clinical use of this method includes positive, differential and etiological diagnosis of tumors, determination of the level of malignancy of gliomas, screening for tumor recurrence following treatment. Our laboratory has been performing MR spectroscopic explorations of brain tumors for many years. Based on this experience, we show how MRS can be routinely performed in the clinical setting, what are its limitations and potential, and what kind of information can be supplied to the clinician.

Impact of the model C and Automatic Positioning System on gamma knife radiosurgery: an evaluation in vestibular schwannomas.

OBJECT: The technical advances associated with the model C gamma knife include a robotized system enabling automatic positioning of the stereotactic coordinates. The purpose of this study was to analyze the clinical impact of this technical modification. METHODS: The authors studied a sample of patients with vestibular schwannoma (VS). This sample included three groups treated using gamma knife radiosurgery. Group I comprised 21 patients with VS treated just before the installation of the Automatic Positioning System (APS). Group II included patients in Group I with new dose plans created using the APS (in other words, simulated dose plans). Group III consisted of a control group of 20 patients matched for tumor grade with the previous group and treated recently with the APS. Treatment times were calculated after correcting the time for each shot according to the age of the sources after reloading. The treatment times, including total time, irradiation time, and duration of the neurosurgical procedure, were analyzed. In addition, dose planning including number of isocenters, number of different collimators, malfunctions, and the conformity and selectivity indices were recorded. The trend was to reduce the mean number of collimator runs from 7.9 to 1.2 and to increase the mean number of shots from 7.9 to 15.6, mostly by using the 4-mm collimator exclusively. The APS-related conformity and selectivity were improved from 95 to 97% and from 78 to 84%, respectively. The total treatment time was reduced by 53%, and time required to interact with the patient in the room was considerably reduced (75%), giving the neurosurgeon greater freedom to perform other tasks during the treatment period. The reduction of the time spent by the neurosurgeon at work in the room was 84%. The total radiation time was increased by 54%. CONCLUSIONS: The preliminary results of this study indicate that the robotization of the gamma knife is likely a major advance in radiosurgery.