Delphine Leclercq

Comparison of diffusion tensor imaging tractography of language tracts and intraoperative subcortical stimulations

OBJECT Diffusion tensor (DT) imaging tractography is increasingly used to map fiber tracts in patients with surgical brain lesions to reduce the risk of postoperative functional deficit. There are few validation studies of DT imaging tractography in these patients. The aim of this study was to compare DT imaging tractography of language fiber tracts by using intraoperative subcortical electrical stimulations. METHODS The authors included 10 patients with low-grade gliomas or dysplasia located in language areas. The MR imaging examination included 3D T1-weighted images for anatomical coregistration, FLAIR, and DT images. Diffusion tensors and fiber tracts were calculated using in-house software. Four tracts were reconstructed in each patient including the arcuate fasciculus, the inferior occipitofrontal fasciculus, and 2 premotor fasciculi (the subcallosal medialis fiber tract and cortical fibers originating from the medial and lateral premotor areas). The authors compared fiber tracts reconstructed using DT imaging with those evidenced using intraoperative subcortical language mapping. RESULTS Seventeen (81%) of 21 positive stimulations were concordant with DT imaging fiber bundles (located within 6 mm of a fiber tract). Four positive stimulations were not located in the vicinity of a DT imaging fiber tract. Stimulations of the arcuate fasciculus mostly induced articulatory and phonemic/syntactic disorders and less frequently semantic paraphasias. Stimulations of the inferior occipitofrontal fasciculus induced semantic paraphasias. Stimulations of the premotor-related fasciculi induced dysarthria and articulatory planning deficit. CONCLUSIONS There was a good correspondence between positive stimulation sites and fiber tracts, suggesting that DT imaging fiber tracking is a reliable technique but not yet optimal to map language tracts in patients with brain lesions. Negative tractography does not rule out the persistence of a fiber tract, especially when invaded by the tumor. Stimulations of the different tracts induced variable language disorders that were specific to each fiber tract.

Clinical trial of blood-brain barrier disruption by pulsed ultrasound

An implantable ultrasound device safely disrupts the blood-brain barrier in glioblastoma patients. A sound attack on brain tumors Brain tumors are difficult to treat with chemotherapy because the blood-brain barrier greatly limits the delivery of drugs into the brain. Carpentier et al. have developed a pulsed ultrasound device, which they implanted into the skull of patients with glioblastoma, an aggressive and difficult to treat brain tumor, in a first-in-human trial. At regularly scheduled treatment sessions, the researchers activated the ultrasound device by connecting it to a power source, disrupting the blood-brain barrier long enough for subsequent chemotherapy to reach the brain. The authors confirmed that this approach was well tolerated and showed evidence of effectiveness to disrupt the blood-brain barrier, paving the way for further development of this therapeutic approach. The blood-brain barrier (BBB) limits the delivery of systemically administered drugs to the brain. Methods to circumvent the BBB have been developed, but none are used in standard clinical practice. The lack of adoption of existing methods is due to procedural invasiveness, serious adverse effects, and the complications associated with performing such techniques coincident with repeated drug administration, which is customary in chemotherapeutic protocols. Pulsed ultrasound, a method for disrupting the BBB, was shown to effectively increase drug concentrations and to slow tumor growth in preclinical studies. We now report the interim results of an ultrasound dose-escalating phase 1/2a clinical trial using an implantable ultrasound device system, SonoCloud, before treatment with carboplatin in patients with recurrent glioblastoma (GBM). The BBB of each patient was disrupted monthly using pulsed ultrasound in combination with systemically injected microbubbles. Contrast-enhanced magnetic resonance imaging (MRI) indicated that the BBB was disrupted at acoustic pressure levels up to 1.1 megapascals without detectable adverse effects on radiologic (MRI) or clinical examination. Our preliminary findings indicate that repeated opening of the BBB using our pulsed ultrasound system, in combination with systemic microbubble injection, is safe and well tolerated in patients with recurrent GBM and has the potential to optimize chemotherapy delivery in the brain.

CSF tau markers are correlated with hippocampal volume in Alzheimer's disease

Hippocampal atrophy as assessed by magnetic resonance imaging (MRI) and abnormal cerebrospinal fluid (CSF) biomarkers are supportive features for the diagnosis of Alzheimers disease (AD) and are assumed to be indirect pathological markers of the disease. In AD patients, antemortem MRI hippocampal volumes (HVs) correlate with the density of neurofibrillary tangles (but not with senile plaques) at autopsy suggesting that HVs may better correlate with CSF tau and hyperphosphorylated tau (P-tau) levels than CSF amyloid beta protein (Aβ)(42) level. Here, we tested this hypothesis in a well-defined AD group. Patients were selected according to the New Research Criteria for AD, including specific episodic memory deficit and CSF AD profile (defined as abnormal ratio of Aβ(42):tau). MRI was performed within 6 months of lumbar puncture. HVs were obtained using automated segmentation software. Thirty-six patients were included. Left HV correlated with CSF tau (R = -0.53) and P-tau (R = -0.56) levels. Mean HVs correlated with the CSF P-tau level (R = -0.52). No correlation was found between any brain measurement and CSF Aβ(42) level. The CSF tau and P-tau levels, but not the CSF Aβ(42) level, correlated with HV, suggesting that CSF tau markers reflect the neuronal loss associated with the physiopathological process of AD.

Diffusion Tractography: Methods, Validation and Applications in Patients with Neurosurgical Lesions

Diffusion tensor imaging (DTI) tractography is increasingly used in presurgical mapping in tumors located in eloquent areas since it is the only non invasive technique that permits in vivo dissection of white matter tracts. Concordance between the DTI tracts and subcortical electrical intraoperative mapping is high, and DTI tractography has proven useful to guide surgery. However, it presents limitations due to the technique and the tumor, which must be known before using the images in the operative room. This review focuses on the possibilities and limits of DTI imaging in intraoperative tumoral mapping and presents an overview of current knowledge.

Social Cognition and Emotional Assessment (SEA) is a Marker of Medial and Orbital Frontal Functions: A Voxel-Based Morphometry Study in Behavioral Variant of Frontotemporal Degeneration

The aim of this study was to explore the cerebral correlates of functional deficits that occur in behavioral variant frontotemporal dementia (bvFTD). A specific neuropsychological battery, the Social cognition & Emotional Assessment (SEA; Funkiewiez et al., 2012), was used to assess impaired social and emotional functions in 20 bvFTD patients who also underwent structural MRI scanning. The SEA subscores of theory of mind, reversal-learning tests, facial emotion identification, and apathy evaluation were entered as covariates in a voxel-based morphometry analysis. The results revealed that the gray matter volume in the rostral part of the medial prefrontal cortex [mPFC, Brodmann area (BA) 10] was associated with scores on the theory of mind subtest, while gray matter volume within the orbitofrontal (OFC) and ventral mPFC (BA 11 and 47) was related to the scores observed in the reversal-learning subtest. Gray matter volume within BA 9 in the mPFC was correlated with scores on the emotion recognition subtest, and the severity of apathetic symptoms in the Apathy scale covaried with gray matter volume in the lateral PFC (BA 44/45). Among these regions, the mPFC and OFC cortices have been shown to be atrophied in the early stages of bvFTD. In addition, SEA and its abbreviated version (mini-SEA) have been demonstrated to be sensitive to early impairments in bvFTD (Bertoux et al., 2012). Taken together, these results suggest a differential involvement of orbital and medial prefrontal subregions in SEA subscores and support the use of the SEA to evaluate the integrity of these regions in the early stages of bvFTD.

Late onset radiation-induced camptocormia

Dear Sirs,Classical causes for camptocormia include amyotrophiclateral sclerosis (ALS), muscle diseases, parkinsonism, andidiopathic cases. We describe a patient who developedtypical camptocormia 7 years after having receivedextended-field radiotherapy.In 1982 a 78-year-old man was diagnosed with follicularlymphoma. He received CHOP (cyclophosphamide, hy-droxydaunorubicin, oncovin, and prednisone) chemother-apy to treat left supraclavicular adenopathy followed byextended-field mantle radiotherapy bilaterally to the axil-lary and subclavicular lymph node areas (40 Gray, 20fractions over 28 days at 5 MV photons). In 1987, relapseoccurred in the iliac area and the patient received a secondcourse of radiation treatment (mediastinal area, spleen,lumboaortic lymph nodes area, bilateral inguinal and iliaclymph nodes areas, 40 Gray, 25 fractions over 25 days). In2001, he relapsed again and received R-CHOP (Rituximab-CHOP). Since then, he has been in clinical remission.He came to our clinic in 2005, with 11 years of pro-gressive camptocormia and lower limb weakness thatinsidiously appeared in 1994; he was 63. He had no familyhistory of neuromuscular disease and had taken no partic-ular drugs (i.e., neuroleptics). Marked camptocormia(Fig. 1) was associated with atrophy and weakness in allparaspinal, cervical, and dorsolumbar muscles and in thebilateral and symmetrical proximodistal lower limbs. Therewere also fasciculations, distal hypoesthesia, and minimalstretch reflexes in the lower limbs. The last follow-up was

Neuroimaging features in posterior reversible encephalopathy syndrome: A pictorial review

Posterior reversible encephalopathy syndrome (PRES) is a radioclinical entity associating nonspecific neurological symptoms (headache, seizures, impairment of alertness, visual disturbances…) occurring in evocative clinical condition (hypertension, eclampsia, immunosuppressor agents, systemic lupus erythematosus…). In the acute stage, the typical imaging finding is a vasogenic edema predominant in the subcortical parietal-occipital white matter. The purpose of this pictorial review is to illustrate the different neuroimaging features of PRES and present key radiological elements to assert diagnosis. In this overview, we examine the following points: the distributions of vasogenic edema, hemorrhage, the varying patterns in diffusion and perfusion, the different types of enhancement encountered and the vascular modifications demonstrated by angiography. The cause of PRES is still unknown. Nevertheless, catheter angiography, MR angiography and MR perfusion features in PRES render further insight into its pathophysiology. Follow-up imaging shows evidence of radiologic improvement in the very large majority of cases in 1 or 2weeks, sometimes in up to 1month. Recurrent PRES attacks are uncommon. Atypical imaging presentation should not reject the diagnosis of PRES in a compatible clinical situation.

Patterns of response and relapse in primary CNS lymphomas after first-line chemotherapy: imaging analysis of the ANOCEF-GOELAMS prospective randomized trial

Background Our aim was to review MRI characteristics of patients with primary CNS lymphoma (PCNSL) enrolled in a randomized phase II trial and to evaluate their potential prognostic value and patterns of relapse, including T2 fluid attenuated inversion recovery (FLAIR) MRI abnormalities. Methods Neuroimaging findings in 85 patients with PCNSL enrolled in a prospective trial were reviewed blinded to outcomes. MRI characteristics and responses according to International PCNSL Collaborative Group (IPCG) criteria were correlated with progression-free survival (PFS) and overall survival (OS). Results Multivariate analysis showed that objective response at 2 months (P < .001) and at end of treatment (P = .015) were predictors of prolonged OS. Infratentorial location (P = .008) and large (>11.4 cm3) enhancing tumor volume (P = .006) were associated with poor OS and PFS, respectively. Ratio of change in product of largest diameters at early MRI evaluation but not timing of complete response achievement (early vs delayed) was prognostic for OS. Sixty-nine patients relapsed. Relapse in the brain (n = 52) involved an initial enhancing site, a different site, or both in 46%, 40%, and 14% of patients, respectively. At baseline, non-enhancing T2-FLAIR hypersignal lesions distant from the enhancing tumor site were detected in 18 patients. These lesions markedly decreased (>50%) in 16 patients after chemotherapy, supporting their neoplastic nature. Of these patients, 10/18 relapsed, half (n = 5) in the initially non-enhancing T2-FLAIR lesions. Conclusions Baseline tumor size and infratentorial localization are of prognostic value in PCNSL. Our findings provide evidence that non-enhancing FLAIR abnormalities may add to overall tumor burden, suggesting that response criteria should be refined to incorporate evaluation of T2-weighted/FLAIR sequences.

Transdifferentiation of Neuroendocrine Cells: Gangliocytoma Associated With Two Pituitary Adenomas of Different Lineage in Men1

Gangliocytomas are rare and benign neuronal cell tumors, mostly found in the hypothalamic and sellar regions. Their histogenesis is still the subject of discussions. Herein we present a unique case of a pituitary gangliocytoma associated with a prolactinoma and a corticotroph adenoma in a patient affected by MEN1. The histologic study revealed shared features between adenomatous and neuronal cells, supporting the etiological hypothesis of a common origin or a phenomenon of transdifferentiation. Furthermore, gangliocytoma could be a new tumor related to MEN1. The clinical and histologic observations are discussed and the literature on the topic is reviewed.

Temporary disruption of the blood-brain barrier using an implantable ultrasound system for recurrent glioblastoma patients under IV carboplatin chemotherapy: initial phase 1/2a clinical trial observations

One of the main limitations to the efficacy of chemotherapy in the brain is the blood-brain barrier (BBB). Previous pre-clinical studies have demonstrated that disruption of the BBB using pulsed ultrasound in combination with an ultrasound microbubble contrast agent can significantly increase the concentration of chemotherapy agents in the brain. Our group has developed an implantable, MR compatible ultrasound device for temporarily disrupting the BBB. The safety of repeated disruption of the BBB using such a device was previously demonstrated in a long-term safety study in four non-human primates. The purpose of this work was to determine the safety and potential efficacy of temporarily disrupting the BBB in patients with recurrent glioblastoma before chemotherapy administration in a first-in-man clinical trial.