Surgery for glioblastomas in the elderly: an Association des Neuro-oncologues d'Expression Française (ANOCEF) trial.

OBJECTIVE: The role of surgery in the treatment of malignant gliomas in the elderly is not settled. The authors conducted a randomized trial that compared tumor resection with biopsy only-both followed by standard therapy-in such patients. METHODS: Patients ≥ 70 years of age with a Karnofsky Performance Scale (KPS) score ≥ 50 and presenting with a radiological suspicion of operable glioblastoma (GBM) were randomly assigned between tumor resection and biopsy groups. Subsequently, they underwent standard radiotherapy during the first years of the trial (2008-2017), with the addition of adjunct therapy with temozolomide when this regimen became standard (2017-2019). The primary endpoint was survival, and secondary endpoints were progression-free survival (PFS), cognitive status (Mini-Mental State Examination), autonomy (KPS), quality of life (European Organisation for Research and Treatment of Cancer [EORTC] QLQ-C30 and QLQ-BN20), and perioperative morbidity and mortality. RESULTS: Between 2008 and 2019, 107 patients from 9 centers were enrolled in the study; 101 were evaluable for analysis because a GBM was histologically confirmed (50 in the surgery arm and 51 in the biopsy arm). There was no statistically significant difference in median survival between the surgery (9.37 months) and the biopsy (8.96 months, p = 0.36) arms (adjusted HR 0.79, 95% CI 0.52-1.21, p = 0.28). However, the surgery group had an increased PFS (5.06 vs 4.02 months; p = 0.034) (adjusted HR 0.50, 95% CI 0.32-0.78, p = 0.002). Less deterioration of quality of life and KPS score evolution than in the biopsy group was observed. Surgery was not associated with increased mortality or morbidity. CONCLUSIONS: This study suggests that debulking surgery is safe, and-compared to biopsy-is associated with a less severe deterioration of quality of life and autonomy, as well as a significant although modest improvement of PFS in elderly patients suffering from newly diagnosed malignant glioma. Although resection does not provide a significant survival benefit in the elderly, the authors believe that the risk/benefit analysis favors an attempt at optimal tumor resection in this population, provided there is careful preoperative geriatric evaluation. Clinical trial registration no.: NCT02892708 (ClinicalTrials.gov).

Combining Awake Anesthesia with Minimal Invasive Surgery Optimizes Intraoperative Surgical Spinal Cord Stimulation Lead Placement.

Spinal cord stimulation (SCS) is an effective and validated treatment to address chronic refractory neuropathic pain in persistent spinal pain syndrome-type 2 (PSPS-T2) patients. Surgical SCS lead placement is traditionally performed under general anesthesia due to its invasiveness. In parallel, recent works have suggested that awake anesthesia (AA), consisting of target controlled intra-venous anesthesia (TCIVA), could be an interesting tool to optimize lead anatomical placement using patient intra-operative feedback. We hypothesized that combining AA with minimal invasive surgery (MIS) could improve SCS outcomes. The goal of this study was to evaluate SCS lead performance (defined by the area of pain adequately covered by paraesthesia generated via SCS), using an intraoperative objective quantitative mapping tool, and secondarily, to assess pain relief, functional improvement and change in quality of life with a composite score. We analyzed data from a prospective multicenter study (ESTIMET) to compare the outcomes of 115 patients implanted with MIS under AA (MISAA group) or general anesthesia (MISGA group), or by laminectomy under general anesthesia (LGA group). All in all, awake surgery appears to show significantly better performance than general anesthesia in terms of patient pain coverage (65% vs. 34-62%), pain surface (50-76% vs. 50-61%) and pain intensity (65% vs. 35-40%), as well as improved secondary outcomes (quality of life, functional disability and depression). One step further, our results suggest that MISAA combined with intra-operative hypnosis could potentialize patient intraoperative cooperation and could be proposed as a personalized package offered to PSPS-T2 patients eligible for SCS implantation in highly dedicated neuromodulation centers.

How Should we Use Multicolumn Spinal Cord Stimulation to Optimize Back Pain Spatial Neural Targeting? A Prospective, Multicenter, Randomized, Double-Blind, Controlled Trial (ESTIMET Study).

BACKGROUND: Recent studies have highlighted multicolumn spinal cord stimulation (SCS) efficacy, hypothesizing that optimized spatial neural targeting provided by new-generation SCS lead design or its multicolumn programming abilities could represent an opportunity to better address chronic back pain (BP). OBJECTIVE: To compare multicolumn vs. monocolumn programming on clinical outcomes of refractory postoperative chronic BP patients implanted with SCS using multicolumn surgical lead. MATERIALS AND METHODS: Twelve centers included 115 patients in a multicenter, randomized, double-blind, controlled trial. After randomization, leads were programmed using only one or several columns. The primary outcome was change in BP visual analogic scale (VAS) at six months. All patients were then programmed using the full potential of the lead up until 12-months follow-up. RESULTS: At six months, there was no significant difference in clinical outcomes whether the SCS was programmed using a mono or a multicolumn program. At 12 months, in all patients having been receiving multicolumn SCS for at least six months (n = 97), VAS decreases were significant for global pain (45.1%), leg pain (55.8%), and BP (41.5%) compared with baseline (p < 0.0001). CONCLUSION: The ESTIMET study confirms the significant benefit experienced on chronic BP by patients implanted with multicolumn SCS, independently from multicolumn lead programming. These good clinical outcomes might result from the specific architecture of the multicolumn lead, giving the opportunity to select initially the best column on a multicolumn grid and to optimize neural targeting with low-energy requirements. However, involving more columns than one does not appear necessary, once initial spatial targeting of the "sweet spot" has been achieved. Our findings suggest that this spatial concept could also be transposed to cylindrical leads, which have drastically improved their capability to shape the electrical field, and might be combined with temporal resolution using SCS new modalities.

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.

Neoadjuvant chemotherapy may optimize the extent of resection of World Health Organization grade II gliomas: a case series of 17 patients.

The involvement of eloquent brain areas may preclude the total/subtotal surgical resection of diffuse low-grade gliomas (DLGGs). The feasibility and functional tolerance of neoadjuvant chemotherapy have been demonstrated in such cases. The present study assesses the clinical and radiological impact of neoadjuvant chemotherapy on the natural course of DLGG. Seventeen patients without feasible surgical resection (infiltration of functional areas and/or large contralateral extension) were retrospectively selected. Temozolomide based neoadjuvant chemotherapy was initiated, inducing a tumor volume decrease and allowing a functional based maximal surgical resection. The median follow-up since initial radiological diagnosis was 5.9 years (range, 1.4-11). The median time to malignant transformation was 5.9 years. Six patients (35 %) had 1p19q codeletion, 12 patients (70 %) with IDH mutation and MGMT promoter methylation, and eight patients (47 %) had p53 overexpression. Chemotherapy reduced tumor volume (median -35.6 %, range -61.6 to -5.1 %) in contralateral hemisphere through the corpus callosum in seven cases (41 %) and in ipsi-lesional functional areas in ten cases (59 %). Chemotherapy significantly decreased the imaging tumor growth (measured by the velocity of diametric expansion VDE) with a median of -3.2 mm/year (range, -29.8 to -0.9 mm/year) (p < 0.001). A tumor volume decrease of more than 20 % was correlated with a lower postoperative residual tumor (median 2 cc, p = 0.04), a greater extent of resection (93.1 vs. 89.5 %), a higher probability of total/subtotal removal. Neoadjuvant chemotherapy with Temozolomide could optimize the surgical resection of DLGGs and could impact their natural history. Further large prospective studies with long-term follow-up are needed.

Spontaneous and therapeutic prognostic factors in adult hemispheric World Health Organization Grade II gliomas: a series of 1097 cases: clinical article.

OBJECT: The spontaneous prognostic factors and optimal therapeutic strategy for WHO Grade II gliomas (GIIGs) have yet to be unanimously defined. Specifically, the role of resection is still debated, most notably because the actual amount of resection has seldom been assessed. METHODS: Cases of GIIGs treated before December 2007 were extracted from a multicenter database retrospectively collected since January 1985 and prospectively collected since 1996. Inclusion criteria were a patient age ≥ 18 years at diagnosis, histological diagnosis of WHO GIIG, and MRI evaluation of tumor volume at diagnosis and after initial surgery. One thousand ninety-seven lesions were included in the analysis. The mean follow-up was 7.4 years since radiological diagnosis. Factors significant in a univariate analysis (with a p value ≤ 0.1) were included in the multivariate Cox proportional hazard regression model analysis. RESULTS: At the time of radiological diagnosis, independent spontaneous factors of a poor prognosis were an age ≥ 55 years, an impaired functional status, a tumor location in a nonfrontal area, and, most of all, a larger tumor size. When the study starting point was set at the time of first treatment, independent favorable prognostic factors were limited to a smaller tumor size, an epileptic symptomatology, and a greater extent of resection. CONCLUSIONS: This large series with its volumetric assessment refines the prognostic value of previously stressed clinical and radiological parameters and highlights the importance of tumor size and location. The results support additional arguments in favor of the predominant role of resection, in accordance with recently reported experiences.

Velocity of tumor spontaneous expansion predicts long-term outcomes for diffuse low-grade gliomas.

BACKGROUND: Supratentorial diffuse low-grade gliomas present a slow macroscopic tumor growth that can be quantified through the measurement of their velocity of diametric expansion. We assessed whether spontaneous velocity of diametric expansion can predict long-term outcomes as a categorical variable and as a continuous predictor. METHODS: A total of 407 adult patients with newly diagnosed supratentorial diffuse low-grade gliomas in adults were studied. RESULTS: The mean spontaneous velocity of diametric expansion before first-line treatment was 5.8 ± 6.3 mm/year. During the follow-up (mean, 86.5 ± 59.4 months), 209 patients presented a malignant transformation, and 87 died. The malignant progression-free survival and the overall survival were significantly longer in cases of slow velocity of diametric expansion (median, 103 and 249 months, respectively) than in cases of fast velocity of diametric expansion (median, 35 and 91 months, respectively; P < .001). In multivariate analyses, spontaneous velocity of diametric expansion as a categorical variable (<4, ≥4 and <8, ≥8 and <12, ≥12 mm/year) was an independent prognostic factor for malignant progression-free survival (P < .001; hazard ratio, 3.87; 95% confidence interval [CI], 2.67-5.52) and for overall survival (P < .001; hazard ratio, 4.62; 95% CI, 2.58-7.97). Velocity of diametric expansion was also an independent prognostic factor for overall survival as a continuous predictor, showing a linear relationship between overall survival and spontaneous velocity of diametric expansion (hazard ratio, 1.09 per one unit increase; 95% CI, 1.06-1.12; P < .001). CONCLUSIONS: Independent of the molecular status, the spontaneous velocity of diametric expansion allows the identification of rapidly growing diffuse low-grade gliomas (at higher risk of worsened evolution) during the pretherapeutic period and without delaying treatment.

Fractionated stereotactic radiotherapy for acoustic neuromas: a prospective monocenter study of about 158 cases.

PURPOSE: To evaluate long-term outcomes and efficacy of fractionated stereotactic radiotherapy in the treatment of acoustic neuromas. MATERIAL AND METHODS: Between January 1996 and December 2009, 158 acoustic neuromas were treated by FSR in 155 patients. They received a dose of 50.4 Gy, with a safety margin of 1-2mm with a median tumor volume at 2.45 mL (range: 0.17-12.5 mL) and a median follow-up duration at 60 months (range: 24-192). RESULTS: FSR was well tolerated in all patients with mild sequelae consisting in radiation-induced trigeminal nerve impairments (3.2%), Grade 2 facial neuropathies (2.5%), new or aggravated tinnitus (2.1%) and VP shunting (2.5%). The treatment failed in four patients (2.5%) who had subsequent surgery respectively at 20, 38, 45 and 84 months post-FSR. The local tumor control rates were respectively 99.3%, 97.5% and 95.2% at 3, 5 and >7-year of follow-up. For initial Gardner-Robertson Grade 1 and 2 ANs, the preservation of useful hearing was possible in 54% of the cases; only Grade 1 ANs had stabilized during the course of the follow-up with 71% >7 years. However, hearing preservation was not correlated to the initial Koos Stage and to the radiation dose delivered to the cochlea. Tinnitus (70%), vertigo (59%), imbalance (46%) and ear mastoid pain (43%) had greatly improved post-FRS in most patients. Tumor control, hearing preservation and FRS toxicity were quite similar in patients with NF2, cystic acoustic neuroma, prior surgical resection and Koos Stage 4 AN. No secondary tumors were observed. CONCLUSION: FSR is a safe and effective therapeutic for acoustic neuromas and could be an alternative to microsurgery. Compared to radiosurgery, there are no contraindications for fractioned doses of stereotactic radiotherapy especially for Stage-4 tumors and patients at high risk of hearing loss.

Implanted carmustine wafers followed by concomitant radiochemotherapy to treat newly diagnosed malignant gliomas: prospective, observational, multicenter study on 92 cases.

OBJECTIVES: Study the feasibility and effectiveness of a treatment associated surgery, intraoperative chemotherapy (carmustine wafers), and concomitant radiochemotherapy (temozolomide) for the management of newly diagnosed, high-grade gliomas. METHODS: Prospective multicenter study conducted in 17 French centers with a total of 92 patients with newly diagnosed malignant glioma treated by surgery, implanted Carmustine wafers (Gliadel(®)) followed by concomitant radiochemotherapy by temozolomide (Temodar(®)). Clinical, imaging, and survival data were collected to study toxicity-induced adverse events and efficacy. RESULTS: A total of 20.6 % presented with adverse events during surgery, potentially attributable to carmustine, including 5 severe infections. Afterwards, 37.2 % of patients showed adverse events during radiochemotherapy and 40 % during adjuvant chemotherapy by temozolomide. We report a 10.5-month, median, progression-free survival and an 18.8-month median overall survival. No significant statistical difference was observed according to age, Karnofsky Performance Scale, or grade of the tumor. A prognostic difference at the limit of the significance threshold was observed according to the extent of the resection. CONCLUSIONS: Multimodal treatment associating implanted carmustine chemotherapy and concomitant radiochemotherapy with temozolomide seems to yield better survival rates than those usually described when carmustine or temozolomide are used alone independently from one another. These interesting results were obtained without increased adverse events and would need to be validated during a phase 3 study.

Natural history of incidental World Health Organization grade II gliomas.

OBJECTIVE: Seizure is the presenting symptom in most of World Health Organization grade II gliomas (GIIGs). Rarely, a GIIG is discovered incidentally on imaging. Little is known about the natural course and prognosis of incidental GIIGs. The aim of the present study is to characterize their natural history and to investigate whether their clinical and radiological behaviors differ from those of symptomatic GIIGs. METHODS: The clinical and radiological findings, treatments, and outcomes of 47 histologically-proven incidental GIIGs were compared with those of 1249 symptomatic GIIGs. RESULTS: Incidental GIIGs differ significantly from symptomatic GIIGs: they have a female predominance (p = 0.05), smaller initial tumor volumes (p < 0.001), lower incidence of contrast enhancement (p = 0.009), and are more likely to undergo gross total surgical removal (p < 0.001). Proliferation rates were similar to that observed among symptomatic GIIGs. Younger age at the time of discovery, frontal lobes, and noneloquent brain regions were associated with incidental GIIGs, as compared to their symptomatic counterparts. When not treated, incidental GIIGs demonstrated radiological growth (median velocity of diametric expansion at 3.5 mm/year), and became symptomatic at a median interval of 48 months after radiological discovery. Overall, incidental discovery was associated with a significant survival benefit (p = 0.04). INTERPRETATION: Incidental GIIGs are progressive tumors leading to clinical transformation toward symptomatic GIIGs. They may represent an earlier step in the natural history of a glioma than the symptomatic GIIGs.

Pregnancy increases the growth rates of World Health Organization grade II gliomas.

Twelve pregnancies in 11 adult women harboring World Health Organization (WHO) grade II gliomas (GIIGs) prior to pregnancy were reviewed to address whether pregnancy affects tumor growth using a quantitative approach of the radiological velocity of diametric expansion (VDE) on successive magnetic resonance images. VDE was significantly increased during pregnancy as compared to prepregnancy (p < 0.001) and to postdelivery (p = 0.012) periods. Pregnancy increases the radiological growth rates of GIIGs. An increase in seizure frequency was observed concomitantly in 40% of cases and further oncological treatment was started after delivery in 25% of cases.

Inter- and intrapatients comparison of WHO grade II glioma kinetics before and after surgical resection.

Grade II gliomas grow slowly and linearly (at rates about 4 mm/year) before undergoing anaplastic transformation. In order to analyze how surgery may affect radiological grade II glioma kinetics, we restrospectively reviewed our national database searching for patients operated on for a supratentorial grade II glioma between 1997 and 2007. We selected patients with at least two postoperative MRI with a minimal delay of 6 months. For each patient, postoperative residues were segmented on successive MRIs. Velocities of diameter expansion were estimated by linear regression of mean diameter evolution for each patient. Fifty-four patients fulfilled inclusion criteria. Median postoperative follow-up was 1.6 years with, on average, 3.4 MRI examinations per patient. Postoperative growth rates of mean diameter were normally distributed, around a mean value of 4.3 mm/year (SD = 3.2 mm/year). Statistical analysis showed no difference between this distribution and the distribution of preoperative growth rates in a previous series of 143 grade II gliomas. For a subset of 23 patients, delay between first MRI and surgery made it possible to estimate also preoperative growth rates. Intrapatient comparison revealed that growth rates were grossly unchanged for 80% of cases. In summary, inter- and intrapatient comparison of pre- and postoperative growth rates proves that surgery does not change grade II glioma dynamics, thus, acting as a cytoreduction.

Fractionated stereotactic radiotherapy treatment of cavernous sinus meningiomas: a study of 100 cases.

PURPOSE: We discuss our experiences with fractionated stereotactic radiotherapy (FSR) in the treatment of cavernous sinus meningiomas. METHODS AND MATERIALS: From 1995 to 2006, we monitored 100 patients diagnosed with cavernous sinus meningiomas; 84 female and 16 male patients were included. The mean patient age was 56 years. The most common symptoms were a reduction in visual acuity (57%), diplopia (50%), exophthalmy (30%), and trigeminal neuralgia (34%). Surgery was initially performed on 26 patients. All patients were treated with FSR. A total of 45 Gy was administered to the lesion, with 5 fractions of 1.8 Gy completed each week. Patient treatment was performed using a Varian Clinac linear accelerator used for cranial treatments and a micro-multileaf collimator. RESULTS: No side effects were reported. Mean follow-up period was 33 months, with 20% of patients undergoing follow-up evaluation of more than 4 years later. The tumor control rate at 3 years was 94%. Three patients required microsurgical intervention because FSR proved ineffective. In terms of functional symptoms, an 81% improvement was observed in patients suffering from exophthalmy, with 46% of these patients being restored to full health. A 52% improvement was observed in diplopia, together with a 67% improvement in visual acuity and a 50% improvement in type V neuropathy. CONCLUSIONS: FSR facilitates tumor control, either as an initial treatment option or in combination with microsurgery. In addition to being a safe procedure with few side effects, FSR offers the significant benefit of superior functional outcomes.

Prognostic significance of imaging contrast enhancement for WHO grade II gliomas.

In this study, we investigated the prognostic value of MRI contrast enhancement (CE) at the time of histological diagnosis specifically in a selected population of WHO grade II gliomas. We reviewed 927 histologically proven WHO grade II gliomas for which contrast-enhanced MR images were available at the time of histological diagnosis. CE patterns were classified into three categories: "patchy and faint," "nodular-like," and "ring-like." CE progression over time was recorded before oncological treatment on successive MR images, when available. CE was present in 143 cases (15.9%), with 93 patchy and faint, 50 nodular-like, and no ring-like patterns. CE areas were time progressive before oncological treatment in 35 of the 56 available cases (62.5%). Regardless of its pattern, the presence of CE was not significantly associated with a worsened prognosis (p = 0.415) by univariate analysis. Only the nodular-like pattern of CE (p < 0.01) and the time-progressive CE (p < 0.001) in the available subgroup proved to be statistically associated with survival since first oncological treatment. The present results show the necessity, in cases of WHO grade II gliomas, to study CE at the time of histological diagnosis and, whenever possible, to follow its progression over time before oncological treatment. Nodular-like CE and time-progressive CE are associated with a worsened prognosis, both suggesting malignant transformation, even though histopathological examination cannot initially disclose signs of malignancy in those areas.

Surgical treatment by electrical stimulation of the auditory cortex for intractable tinnitus.

Tinnitus is a public health issue in France. Around 1% of the population is affected and 30,000 people are handicapped in their daily life. The treatments available for disabling tinnitus have until now been disappointing. We are reporting on the surgical treatment by electrical stimulation of the auditory cortex of a female patient affected by disabling tinnitus that resisted classical treatments. The tinnitus appeared suddenly 10 years ago after a left ear tympanoplasty. The acouphenometry measures revealed a bilateral tinnitus, predominant on the right side, constant, with high frequency (6000 Hz). Transcranial magnetic stimulation (TMS) was performed at first with several supraliminal and infraliminal protocols. This showed promising results. Anatomic and functional magnetic resonance imaging (fMRI) of the auditory cortex before and after repetitive TMS (rTMS) demonstrated a modification of the cortical activity and where the ideal location for a cortical electrode might be, to straddle primary and secondary auditory cortex. After these investigations, two quadra polar electrodes (Resume, Medtronic Ltd, Hertfordshire, UK), connected to a stimulating device implanted under the skin (Synergy, Medtronic Ltd), were extradurally implanted. The surgical procedure was similar to the one performed for analgesic cortical stimulation. No surgical complications were reported. The activation of the stimulator provided a reduction of 65% of the tinnitus impact, with a persistent effect on the right side. The feasibility of the cortical stimulation in symptomatic treatment of tinnitus was proven by this preparatory work. The middle- and long-term therapeutic effects remain to be evaluated.

Attenuation of the blood flow response to physostigmine in the rat cortex deafferented from the basal forebrain.

Previous functional investigations in rats failed to demonstrate that the classical cholinesterase inhibitor, physostigmine, can compensate for cortical cholinergic deficit induced by deafferentation from the nucleus basalis magnocellularis (NBM). As these studies were carried out shortly after NBM lesion (1-2 weeks), we sought to determine whether compensatory effects of physostigmine would appear at a longer postlesion time (3-5 weeks). Cerebral blood flow was used as a quantitative measure of brain function. At 3-5 weeks after unilateral NBM lesion, interhemispheric comparisons in resting conditions showed that the cortical cholinergic deficit was still present and that blood flow was lower in cortical areas on the lesion side, similarly to what was observed after 1-2 weeks, while basal blood flow in intact hemispheres remained unchanged. In contrast, under physostigmine, blood flow became significantly lower in deafferented cortical areas at 3-5 weeks postlesion time, whereas there were no significant interhemispheric differences in the short term. Comparisons with saline-infused rats showed reduced blood flow responses to physostigmine in forebrain regions, e.g. in the parietal cortex from 83% to 25% at 1-2 and 3-5 weeks postlesion, respectively. These changes cannot be ascribed to a global loss of reactivity, since responses in brainstem regions (medulla, cerebellum) remained unchanged statistically. The results demonstrate a reduced responsiveness to physostigmine at the longer postlesion time, and support the existence of a cholinosensitive mechanism antagonizing NBM influence. This mechanism may limit the activating effects of cholinergic agonists in the forebrain after NBM deafferentation.

Treatment of pituitary adenomas by fractionated stereotactic radiotherapy: a prospective study of 110 patients.

PURPOSE: To optimize and reduce the toxicity of pituitary adenoma irradiation by assessing the feasibility and effectiveness of fractionated stereotactic radiotherapy (FSR). METHODS AND MATERIALS: Between 1990 and 1999, 110 consecutive patients, 47 with a functioning adenoma, were treated according to a strategy of either early surgery and FSR (n = 89) or FSR only (n = 21). Of the 110 patients, 75 had persistent macroscopic tumor and 47 persistent hormonal secretions; 15 were treated in the prophylactic setting. The linear accelerator-delivered dose was 50.4 Gy (5 x 1.8 Gy weekly), with a 2-mm safety margin. RESULTS: After a minimal follow-up of 48 months, only 1 patient had developed progression. Of the 110 patients, 27 (36%) had a complete tumor response, 67 (89.3%) had an objective tumor response, 20 (42%) had a hormonal complete response, and 47 (100%) had a hormonal objective tumor response. The proportion of patients without a complete tumor response, objective tumor response, complete hormonal response, and objective hormonal response was 85.1%, 62%, 83%, and 59.3% at 4 years and 49.3%, 9%, 59.3%, and 10.6% at 8 years, respectively. The sole unfavorable predictive factor was preoperative SSE >20 mm for tumor response (p = 0.01) and growth hormone adenoma for the hormonal response (p <0.001). No late complications, except for pituitary deficiency, were reported, with a probability of requiring hormonal replacement of 28.5% and 35% at 4 and 8 years, respectively. Nonfunctioning status was the sole unfavorable factor (p = 0.0016). CONCLUSIONS: Surgery plus FSR is safe and effective. FSR focused to the target volume seems more suitable than standard radiotherapy, and standard fractionation reduces the risk of optic neuropathy sometimes observed after single-dose radiosurgery. Therefore, FSR allows us to consider combined transrhinoseptal surgery and early radiotherapy, with a curative goal without patient selection.

New insights into the anatomo-functional connectivity of the semantic system: a study using cortico-subcortical electrostimulations.

Despite a better understanding of the organization of the cortical network underlying the semantic system, very few data are currently available regarding its anatomo-functional connectivity. Here, we report on a series of 17 patients operated on under local anaesthesia for a cerebral low-grade glioma located within the dominant hemisphere. Prior to and during resection, intraoperative electrical stimulation was used to map sensorimotor and language structures so that permanent neurological deficits could be avoided. In a number of cases, cortical and subcortical stimulation caused semantic paraphasias. Using postoperative MRI, we correlated these functional findings with the anatomical locations of the sites where semantic errors were elicited by stimulation, especially at the subcortical level, with the aim of studying the connectivity underlying the semantic system. In temporal gliomas, cortical sites involved in semantic processing were found around the posterior part of the superior temporal sulcus, with subcortical pathways reproducibly located under the depth of this sulcus. In insular gliomas, although stimulation elicited no semantic disturbances at the cortical level, such semantic paraphasias were generated at the level of the anterior floor of the external capsule. In frontal tumours, cortical regions implicated in semantics were detected in the lateral orbitofrontal region and dorsolateral prefrontal cortex, with subcortical fibres located under the inferior frontal sulcus. All these eloquent structures were systematically preserved, thereby avoiding permanent postoperative deficits. Our results provide arguments in favour of the existence of a main ventral subcortical pathway underlying the semantic system, within the dominant hemisphere, joining the two essential cortical epicentres of this network: the posterior and superior temporal areas, and the orbitofrontal and dorsolateral prefontal regions. Such a ventral stream might anatomically partly correspond to the inferior fronto-occipital fasciculus.

Computer-aided intrapatient comparison of brain SPECT images: the gray-level normalization issue applied to children with epilepsy.

UNLABELLED: A tool was developed for automated intrapatient comparison of brain SPECT images, with specific emphasis on gray-level normalization. METHODS: Ictal and interictal (99m)Tc-ethyl cysteinate dimer SPECT images were acquired for 6 children with partial epilepsy (age range, 2-10 y). For each patient, 3-dimensional rigid geometric ictal-to-interictal image registration optimizing different classic criteria (correlation coefficient, ratio uniformity) in a multiscale translation-rotation 6-parameter space was first performed. Gray-level normalization was then performed with different methods, using a 1- or 2-parameter linear model. In the 1-parameter case, the scaling factor was equal to the interictal-to-ictal ratio of the maximum, mean, or median values calculated within different reference volumes (whole brain or cerebellum) or obtained by linear regression between ictal and interictal counts in the brain or by maximizing a robust criterion, the number of deterministic sign changes in the subtraction images. In the 2-parameter case, the scaling factor and additive constant were estimated using these last 2 methods. For each patient, registration validity and normalization plausibility were assessed by considering the correlation scatterplot together with the different normalization lines and by comparing interictal and registered normalized ictal images using a twin display (with isocontours) in the 3 orthogonal planes. Three-dimensional volumes of interest could be selected on coupled interictal-subtraction images for further focused numeric comparison. RESULTS: After a satisfactory and stable geometric registration with both criteria, the different normalization methods led to similar subtraction images for 5 of 6 patients, except the maxima ratio, which gave noticeably different results in 2 patients. For the remaining patient, with highly dissimilar ictal-interictal images, the maxima ratio normalization was obviously wrong and the other 1-parameter methods probably better depicted the data than did the 2-parameter methods. CONCLUSION: When comparing intrapatient brain SPECT images, one should be aware of the potential impact of the gray-level normalization method on clinical interpretation. For ictal-interictal images, simple robust scaling should be recommended. In particular, image maximum should generally not be considered a valid reference, and no additive constant is needed in the linear gray-level normalization model.