A case report of agoraphobia following right parietal lobe surgery: changes in functional and structural connectivities of the multimodal vestibular network.

Agoraphobia is a visuo-vestibular-spatial disorder that may involve dysfunction of the vestibular network, which includes the insular and limbic cortex. We sought to study the neural correlates of this disorder in an individual who developed agoraphobia after surgical removal of a high-grade glioma located in the right parietal lobe, by assessing pre- and post-surgery connectivities in the vestibular network. The patient underwent surgical resection of the glioma located within the right supramarginal gyrus. The resection interested also portions of the superior and inferior parietal lobe. Structural and functional connectivities were assessed through magnetic resonance imaging before and 5 and 7 months after surgery. Connectivity analyses focused on a network comprising 142 spherical regions of interest (4 mm radius) associated with the vestibular cortex: 77 in the left and 65 in the right hemisphere (excluding lesioned regions). Tractography for diffusion-weighted structural data and correlation between time series for functional resting-state data were calculated for each pair of regions in order to build weighted connectivity matrices. Graph theory was applied to assess post-surgery changes in network measures, such as strength, clustering coefficient, and local efficiency. Structural connectomes after surgery showed a decrease of strength in the preserved ventral portion of the supramarginal gyrus (PFcm) and in a high order visual motion area in the right middle temporal gyrus (37dl), and decrease of the clustering coefficient and of the local efficiency in several areas of the limbic, insular cortex, parietal and frontal cortex, indicating general disconnection of the vestibular network. Functional connectivity analysis showed both a decrease in connectivity metrics, mainly in high-order visual areas and in the parietal cortex, and an increase in connectivity metrics, mainly in the precuneus, parietal and frontal opercula, limbic, and insular cortex. This post-surgery reorganization of the vestibular network is compatible with altered processing of visuo-vestibular-spatial information, yielding agoraphobia symptoms. Specifically, post-surgical functional increases of clustering coefficient and local efficiency in the anterior insula and in the cingulate cortex might indicate a more predominant role of these areas within the vestibular network, which could be predictive of the fear and avoiding behavior characterizing agoraphobia.

Homotopic redistribution of functional connectivity in insula-centered diffuse low-grade glioma.

OBJECTIVE: In the event of neural injury, the homologous contralateral brain areas may play a compensatory role to avoid or limit the functional loss. However, this dynamic strategy of functional redistribution is not clearly established, especially in the pathophysiological context of diffuse low-grade glioma. Our aim here was to assess the extent to which unilateral tumor infiltration of the insula dynamically modulates the functional connectivity of the contralesional one. METHODS: Using resting-state functional connectivity MRI, a seed-to-ROI approach was employed in 52 insula-centered glioma patients (n = 30 left and 22 right) compared with 19 age-matched healthy controls. RESULTS: Unsurprisingly, a significant decrease of the inter-insular connectivity was observed in both patient groups. More importantly, the analyses revealed a significant increase of the contralesional insular connectivity towards both cerebral hemispheres, especially in cortical areas forming the visual and the sensorimotor networks. This functional redistribution was not identified when the analyses were performed on three control regions for which the homologous area was not impaired by the tumor. This overall pattern of results indicates that massive infiltration of the insular cortex causes a significant redeployment of the contralesional functional connectivity. CONCLUSION: This general finding suggests that the undamaged insula plays a role in the functional compensation usually observed in this patient population, and thus provides compelling support for the concept of homotopic functional plasticity in brain-damaged patients.

Neuropsychological assessments before and after awake surgery for incidental low-grade gliomas.

OBJECTIVE: Early surgery in presumed asymptomatic patients with incidental low-grade glioma (ILGG) has been suggested to improve maximal resection rates and overall survival. However, no study has reported on the impact of such preventive treatment on cognitive functioning. The aim of this study was to investigate neuropsychological outcomes in patients with ILGG who underwent preventive surgery. METHODS: This was a retrospective analysis of a consecutive series of patients with ILGG who underwent awake surgery and who had presurgical and 3-month postsurgical neuropsychological assessments. Data were normalized into z-scores and regrouped by cognitive domains. Clinicoradiological data, histomolecular profile, and differences in z-scores (Δz-scores) were analyzed. RESULTS: Forty-seven patients were included (mean age 39.2 ± 11.3 years). Twenty-eight patients (59.6%) underwent supratotal or total resections. All patients were still alive after a mean follow-up of 33.0 ± 30.8 months. Forty-one patients (87.2%) had stable (n = 34, 72.3%) or improved (Δz-score > 1; n = 7, 14.9%) neurocognitive outcomes after surgery. Six patients (12.8%) presented a slight impairment (Δz-score < -1) in at least one cognitive domain. The mean presurgical and postsurgical z-scores were comparable except in the psychomotor speed and attention domain. A significant correlation between presurgical executive functioning and tumor volume was reported, whereas the extent of resection and histomolecular profile did not impact neuropsychological outcomes. CONCLUSIONS: Early surgical treatment in presumed asymptomatic patients with ILGG was associated with stable or improved neuropsychological outcomes in 87.2% of patients at 3 months, with only mild cognitive decline observed in 6 patients. In return, supratotal or total resections were achieved in most patients, and all patients were still alive at the end of the follow-up.

Network-behavior mapping of lasting executive impairments after low-grade glioma surgery.

Executive functions (EF) may be significantly impaired following low-grade glioma (LGG) surgery, especially in the event of white matter (WM) disruption. The aim of this study was to identify the connective tracts associated with EF impairments after LGG surgery, and to provide new insights into the WM network architecture of EF. EF measurements were collected in 270 patients at the chronic postoperative phase. This comprised cognitive flexibility, verbal inhibition and fluency abilities (phonological and categorical). The scores were z-corrected for age and educational level, and further submitted to a principal component analysis (PCA). Tracwise and disconnectome-behavior analyses were then performed using EF measures independently but also the extracted components from PCA. For the first analyses, 15 tracts of interest were selected. Two principal components were extracted from the behavioral data, interpreted as 'EF' and 'language' components. Robust, bonferroni-corrected correlations were established between the EF component and Layers II and III of the left superior longitudinal fasciculus, and between phonological fluency/inhibition and the same tracts. Less powerful but still significant correlations were also observed with the left frontal aslant and fronto-striatal tracts. These results were confirmed by disconnectome-behavior analyses. Our results indicate that surgically-related disruption of the fronto-parietal and the frontal cortico-subcortical connectivity, and of the frontal aslant tract, is related to long-lasting EF impairments. In addition to providing new insights into the WM pathways supporting EF, these findings are especially useful for both surgical planning and the predictive approach of neuropsychological disorders in the context of LGG surgery.

The antero-dorsal precuneal cortex supports specific aspects of bodily awareness.

The precuneus is a functionally heterogeneous area located on the medial face of the parietal cortex, wedged between the occipital cortex and the paracentral lobule. In view of its topological positioning, this associative cortex is well-placed to play an important role in multisensory integration, specific aspects of which participate to bodily awareness. However, this potential implication remains unestablished. We assessed bodily awareness longitudinally in 14 rare patients who underwent a surgery for a low-grade glioma mainly infiltrating the precuneus. To determine the brain locus the most frequently affected in patients showing bodily awareness disorders, we first contrasted the resection cavity distributions of patients with versus without bodily awareness disorders. We next applied 'lesion network mapping' to identify the networks functionally coupled with lesion locations causing bodily awareness disorder. Bodily awareness disorders were observed in half of patients after surgery, especially alien hand, macrosomatognosia and fading limb. Importantly, a dissociation was revealed between the antero-dorsal precuneus (bodily awareness disorders) and postero-dorsal precuneus (no bodily awareness disorders). Furthermore, bodily awareness disorder-related regions were specifically connected to a network of sensorimotor regions while others were connected with the default network. Altogether, the present findings indicate a critical role of the antero-dorsal precuneus in specific aspects of bodily awareness and in the maintenance of body schema.

Combining resting state functional MRI with intraoperative cortical stimulation to map the mentalizing network.

OBJECTIVE: To infer the face-based mentalizing network from resting-state functional MRI (rsfMRI) using a seed-based correlation analysis with regions of interest identified during intraoperative cortical electrostimulation. METHODS: We retrospectively included 23 patients in whom cortical electrostimulation induced transient face-based mentalizing impairment during 'awake' craniotomy for resection of a right-sided diffuse low-grade glioma. Positive stimulation sites were recorded and transferred to the patients' preoperative normalized MRI, and then used as seeds for subsequent seed-to-voxel functional connectivity analyses. The analyses, conducted with an uncorrected voxel-level p-value of 0.001 and a false-discovery-rate cluster-level p-value of 0.05, allowed identification of the cortical structures, functionally coupled with the mentalizing-related sites. RESULTS: Two clusters of responsive stimulations were identified intraoperatively - one in the right dorsolateral prefrontal cortex (dlPFC, n = 13) and the other in the right inferior frontal gyrus (IFG, n = 10). A whole group level analysis revealed that stimulation sites correlated mainly with voxels located in the pars triangularis of the IFG, the dorsolateral and dorsomedial prefrontal cortices, the temporo-parietal junction, the posterior superior temporal sulcus, and the posterior inferior temporal/fusiform gyrus. Other analyses, taking into consideration the location of the responsive sites (IFG versus dlPFC cluster), highlighted only minor differences between both groups. CONCLUSIONS: The present study successfully demonstrated the involvement of a large-scale neural network in the face-based mentalizing that strongly matches networks, classically identified using task-based fMRI paradigms. We thus validated the combination of rsfMRI and stimulation mapping as a powerful approach to identify functional networks in brain-damaged patients.

The enigma of multicentric glioblastoma: physiopathogenic hypothesis and discussion about two cases.

Two men were admitted following generalized seizures. Cerebral MRI-scans showed multiple independent enhancing lesions which were bilateral (first case) and unilateral but disseminated to the brainstem (second case). Whole-body CT-scans showed no primaries. Both cases were diagnosed by biopsy as IDH1 wild-type multicentric glioblastoma. Treatment of both was palliative. The natural history of this entity remains matter of debate but 2 genomic analysis strikingly revealed that foci from the same patient were of monoclonal origin. Consistently, these 2 cases could sustain the hypothesis that an anatomical connectivity exists between the different foci of a multicentric glioblastoma.

Instrumented Circumferential Fusion in Two Stages for Instable Lumbar Fracture: Long-Term Results of a Series of 74 Patients on Sagittal Balance and Functional Outcomes.

OBJECTIVE: To report the radiologic and functional results of a multicenter, prospective case series of patients with comminuted lumbar fractures treated with 2-stage circumferential arthrodesis. METHODS: A multicenter prospective case series of 74 patients with comminuted lumbar fractures was analyzed. The strategy entailed initial posterior osteosynthesis, followed by physical replacement with an expandable titanium cage filled with autologous bone via retroperitoneal lumbotomy. The mechanism of lesion formation and epidemiologic characteristics were recorded. Clinical and quality-of-life analyses (visual analog scale [VAS], Oswesty Disability Index [ODI], Short Form 12 [SF-12]) were performed over a minimum observation period of 1 year. Radiologic parameters, including deformity measurements, were recorded at each evaluation. Fusion was analyzed by means of a 1-year monitoring scan. RESULTS: The mean patient age was 38.1 years, and median duration of follow-up was 2.1 years (interquartile range, 1.3-2.9). The distribution of fractures according to the Magerl classification scheme was as follows: A, 64.8%; B, 16.7%; C, 18.5%. At the last follow-up, fusion was considered certain in 57 cases (77%). The mean VAS score was 2.1 ± 1.3, mean ODI was 14.7 ± 8.0, mean SF-12 Physical Component Summary score was 43.2 ± 9.3, and mean SF-12 Mental Component Summary score was 50.8 ± 5.9. Correction of the regional sagittal deformity was significant during the postoperative period, with a mean increase in lordosis of 9.0° (P < 0.0001). The loss of mean correction at the last follow-up (-2.9°) was not significant. CONCLUSIONS: Circumferential arthrodesis, including posterior osteosynthesis and physical replacement with an expandable cage and autologous graft, is applicable to the treatment of comminuted lumbar fractures. A high rate of fusion was obtained with significant and long-lasting correction of the sagittal deformity. Functional scores measured at 1 year suggest mild disability. The ODI, SF-12, and VAS scores were positively correlated with fusion at the last follow-up.

Comparison between resting state fMRI networks and responsive cortical stimulations in glioma patients.

OBJECTIVES: To validate the functional relevance of resting state networks (RSNs) by means of a comparison of resting state connectivity (RSC) between language regions elicited by direct cortical stimulation versus RSC between random regions; and to evaluate the accuracy of resting state fMRI in surgical planning by assessing the overlap between RSNs and intraoperative functional mapping results. METHODS: Sensorimotor and language eloquent sites were identified by direct electrical cortical stimulation in 98 patients with a diffuse low-grade glioma. A seed to voxel analysis with inter-language stimulation point connectivity versus inter-random ROIs connectivity was performed (19 patients). An independant component analysis (ICA) was also applied to rsfMRI data. Language and sensorimotor components were selected over 20 independent components and compared to the corresponding stimulation points and resected cortex masks (31 and 90 patients, respectively). RESULTS: Mean connectivity value between language seeds was significantly higher than the one between random seeds (0.68 ± 0.39 and 0.12 ± 0.21 respectively, P < 10-10 ). 96 ± 11% of sensorimotor stimulation points were located within 10 mm from sensorimotor ICA maps versus 92 ± 21% for language. 3.1 and 15% of resected cortex overlapped sensorimotor and language networks, respectively. Mean sensorimotor stimulation points and resected cortex z-scores were 2.0 ± 1.2 and -0.050 ± 0.60, respectively (P < 10-10 ). Mean language stimulation points and resected cortex z-scores were 1.6 ± 1.9 and 0.68 ± 0.91, respectively, P < 0.005. CONCLUSION: The significantly higher RSC between language seeds than between random seeds validated the functional relevance of RSC. ICA partly succeeded to distinguish eloquent versus surgically removable areas and may be possibly used as a complementary tool to intraoperative mapping. Hum Brain Mapp 37:3721-3732, 2016. © 2016 Wiley Periodicals, Inc.

[Intrathecal methotrexate in breast cancer meningeal carcinomatosis - Experience with a new administration schedule]. / Méthotrexate intrathécal dans les méningites carcinomateuses du cancer du sein - Expérience avec le protocole utilisé à l'hôpital Saint-Louis.

Methotrexate represents the standard intrathecal treatment of breast cancer meningeal carcinomatosis. However, its optimal schedule remains undefined. The aim of the present study was to evaluate results obtained with the methotrexate schedule used in Saint-Louis hospital (Paris). Patients followed in Saint-Louis hospital for breast cancer and who received intrathecal methotrexate were included in this retrospective monocentric study. Intrathecal treatment received contained methotrexate 12 mg/day (days: 1-5) and then 15 mg/week until progression or toxicity. Between 2003 and 2015, 41 patients were included. Primitive tumours were RH+/HER2-, HER2+ and triple-negative in respectively 66%, 14%, 5% and 15% of patients, 22% of them had meningeal carcinomatosis as metastatic disease initial manifestation. Objective response rate was 54%, median overall survival was 4.0 mois [CI 95%: 3-7.3] and 1-year survival rate was 15.2% (11.4%, 50% et 0% in RH+/HER2-, HER2+ and triple-negative subgroups; HR=0.45 [0.21-0.97] between HER2+ and RH+/HER2-). In univariate analysis, prognostic factors were brain involvement (p=0.049), initial cerebrospinal fluid protein level (p=0.0002) and concomitant systemic treatment received (p=0.049). This intrathecal methotrexate schedule demonstrates a similar median overall survival as the one obtained with a dose-dense schedule and an improved quality of life. Nevertheless, as the objective response and 1-year survival rates are slightly inferior, a dose-dense schedule remains still preferred in HER2+ patients or in those harboring a mainly meningeal progression.

Role of the left frontal aslant tract in stuttering: a brain stimulation and tractographic study.

The neural correlates of stuttering are to date incompletely understood. Although the possible involvement of the basal ganglia, the cerebellum and certain parts of the cerebral cortex in this speech disorder has previously been reported, there are still not many studies investigating the role of white matter fibers in stuttering. Axonal stimulation during awake surgery provides a unique opportunity to study the functional role of structural connectivity. Here, our goal was to investigate the white matter tracts implicated in stuttering, by combining direct electrostimulation mapping and postoperative tractography imaging, with a special focus on the left frontal aslant tract. Eight patients with no preoperative stuttering underwent awake surgery for a left frontal low-grade glioma. Intraoperative cortical and axonal electrical mapping was used to interfere in speech processing and subsequently provoke stuttering. We further assessed the relationship between the subcortical sites leading to stuttering and the spatial course of the frontal aslant tract. All patients experienced intraoperative stuttering during axonal electrostimulation. On postsurgical tractographies, the subcortical distribution of stimulated sites matched the topographical position of the left frontal aslant tract. This white matter pathway was preserved during surgery, and no patients had postoperative stuttering. For the first time to our knowledge, by using direct axonal stimulation combined with postoperative tractography, we provide original data supporting a pivotal role of the left frontal aslant tract in stuttering. We propose that this speech disorder could be the result of a disconnection within a large-scale cortico-subcortical circuit subserving speech motor control.

Acute progression of untreated incidental WHO Grade II glioma to glioblastoma in an asymptomatic patient.

WHO Grade II glioma (low-grade glioma [LGG]) is increasingly diagnosed as an incidental finding in patients undergoing MRI for many conditions. Recent data have demonstrated that such incidental LGGs are progressive tumors that undergo clinical transformation and ultimately become malignant. Although asymptomatic LGG seems to represent an earlier step in the natural course of a glioma than the symptomatic LGG, it is nonetheless impossible to predict at the individual level when the tumor will become malignant. The authors report the case of a 43-year-old woman with a right operculo-insular LGG that was incidentally diagnosed because of headaches. No treatment was proposed, and repeated MRI scans were performed for 6 years in another institution. Due to a slow but continuous growth of the lesion, the patient was finally referred to our center to undergo surgery. Interestingly, objective calculation of the velocity of the tumor's diametric expansion demonstrated a sudden acceleration of the growth rate within the 5 months preceding surgery, with the development of contrast enhancement. Remarkably, the patient was still asymptomatic. An awake resection was performed with intraoperative electrical mapping. There was no functional worsening following surgery, as assessed on postoperative neuropsychological examination. Removal of 92% of signal abnormality on FLAIR MRI was achieved, with complete resection of the area of contrast enhancement. Neuropathological examination revealed a glioblastoma, and the patient was subsequently treated with concomitant radiotherapy and chemotherapy. Although a "wait and see" attitude has been advocated by some authors with respect to incidental LGG, our original case demonstrates that acute transformation to glioblastoma may nonetheless occur, even before the onset of any symptoms. Therefore, because the lack of symptoms does not protect from malignant transformation, we propose consideration of earlier resection in a more systematic manner in cases of incidental LGG.

Patients with incidental WHO grade II glioma frequently suffer from neuropsychological disturbances.

BACKGROUND: Incidental WHO grade II gliomas (low-grade glioma, LGG) are increasingly diagnosed in patients undergoing MRI for many conditions. These patients are classically considered asymptomatic because they do not experience seizures. Although it was previously demonstrated that symptomatic LGG patients frequently have neurocognitive disorders, the literature does not provide data on the neuropsychological status of patients with incidental LGG (iLGG). OBJECTIVE: Our aim is to investigate whether neurocognitive impairments exist in a homogeneous iLGG population. METHODS: We conducted an analysis of pretreatment neuropsychological assessments of patients with iLGG (histologically proven) admitted to our center from 2007 to 2014. We also obtained data on subjective complaints, tumor size and location. RESULTS: Our study focused on 15 iLGG patients. Two thirds reported subjective complaints, mainly tiredness (40 %) and attentional impairment (33 %). Neurocognitive functions were disturbed in 60 % of patients; 53 % had altered executive functions, 20 % had working memory impairment, and 6 % had attentional disturbances. Only one patient with normal preoperative neuropsychological assessment experienced a deficit at the 3-month postoperative examination. CONCLUSIONS: For the first time to our knowledge, we suggest that numerous iLGG patients have neuropsychological impairments. Therefore, greater attention should be paid to objective neuropsychological assessment in iLGG because of the high prevalence of insidious cognitive deficits. Moreover, our original findings bring into question the traditional wait-and-see attitude in iLGG, mainly based on the erroneous dogma that these patients have no functional disturbances. Neuropsychological assessment is mandatory to select the best individualized therapeutic management with preservation of quality of life.