Prognosis of glioblastoma patients improves significantly over time interrogating historical controls.

BACKGROUND: Glioblastoma (GBM) is the most common devastating primary brain cancer in adults. In our clinical practice, median overall survival (mOS) of GBM patients seems increasing over time. METHODS: To address this observation, we have retrospectively analyzed the prognosis of 722 newly diagnosed GBM patients, aged below 70, in good clinical conditions (i.e. Karnofsky Performance Status -KPS- above 70%) and treated in our department according to the standard of care (SOC) between 2005 and 2018. Patients were divided into two groups according to the year of diagnosis (group 1: from 2005 to 2012; group 2: from 2013 to 2018). RESULTS: Characteristics of patients and tumors of both groups were very similar regarding confounding factors (age, KPS, MGMT promoter methylation status and treatments). Follow-up time was fixed at 24 months to ensure comparable survival times between both groups. Group 1 patients had a mOS of 19 months ([17.3-21.3]) while mOS of group 2 patients was not reached. The recent period of diagnosis was significantly associated with a longer mOS in univariate analysis (HR=0.64, 95% CI [0.51 - 0.81]), p < 0.001). Multivariate Cox analysis showed that the period of diagnosis remained significantly prognostic after adjustment on confounding factors (adjusted Hazard Ratio (aHR) 0.49, 95% CI [0.36-0.67], p < 0.001). CONCLUSION: This increase of mOS over time in newly diagnosed GBM patients could be explained by better management of potentially associated non-neurological diseases, optimization of validated SOC, better management of treatments side effects, supportive care and participation in clinical trials.

MRI features of intra-axial histiocytic brain mass lesions.

AIM: To describe MRI features, including diffusion-weighted imaging (DWI), magnetic resonance spectroscopy (MRS), and perfusion-weighted imaging (PWI), of intra-axial tumour-like presentations of four different subtypes of histiocytosis. MATERIAL AND METHODS: The brain MRI findings of 23 patients with histologically proven histiocytosis were reviewed retrospectively (11 Langerhans cell histiocytosis [LCH], eight Erdheim-Chester disease [ECD], one overlap form LCH/ECD, two Rosai-Dorfman disease [RDD], and one haemophagocytic lymphohistiocytosis [HLH]) with single or multiple enhancing intraparenchymal brain lesions. RESULTS: Histiocytic brain mass lesions show some similar MRI features including Supra and/or infratentorial and/or paraventricular subcortical well-delineated masses, linear ependymal enhancement along the ventricles and brain stem lesions. Masses always present with mixed hyper- and hypointense signal on T2-weighted imaging (WI). Their enhancement is often homogeneous. Apparent diffusion coefficient (ADC) values are often normal or elevated. CONCLUSION: The presence of multiple periventricular and subcortical enhancing lesions with mixed signal intensity on T2WI and normal or high ADC values should lead radiologists to consider the diagnosis of histiocytic lesions and search for associated systemic lesions.

[Infection associated cerebral vasculitis]. / Vascularites cérébrales associées aux infections.

Infections are a frequent cause of cerebral vasculitis, important to diagnose because a specific treatment may be required. Infection-associated vasculitis can be caused by angiotropic pathogens (varicella zoster virus, syphilis, aspergillus). They can be associated with subarachnoidal meningitis (tuberculosis, pyogenic meningitis, cysticercosis). They can appear contiguously to sinuses or orbital infection (aspergillosis, mucormycosis). Finally, they also may be due to an immune mechanism in the context of chronic infections (hepatitis B virus, hepatitis C virus, human immunodeficiency virus). Cerebral vasculitis are severe conditions and their prognosis is directly linked to early recognition and diagnosis. Infectious causes must therefore be systematically considered ahead of cerebral vasculitis, and the appropriate investigations must be determined according to the patient's clinical context. We propose here an update on the infectious causes of cerebral vasculitis, their diagnosis modalities, and therapeutic options.

Characterization of Skull Base Lesions Using Pseudo-Continuous Arterial Spin Labeling.

PURPOSE: Pseudo-continuous arterial spin labeling (pCASL) is a non-invasive magnetic resonance (MR) perfusion technique. Our study aimed at estimating the diagnostic performance of the pCASL sequence in assessing the perfusion of skull base lesions both qualitatively and quantitatively and at providing cut-off values for differentiation of specific skull base lesions. METHODS: In this study 99 patients with histopathologically confirmed skull base lesions were retrospectively enrolled. Based on a pathological analysis, the lesions were classified as hypervascular and non-hypervascular. Patients were divided into two subgroups according to the anatomical origin of each lesion. The MRI study included pCASL and 3D T1-weighted fat-saturated post-contrast sequences. Of the patients seven were excluded due to technical difficulties or patient movement. The lesions were classified by two raters, blinded to the diagnosis as either hyperperfused or non-hyperperfused, based on the pCASL sequence. The normalized tumor blood flow (nTBF) of each lesion was determined. Qualitative and quantitative characteristics of hypervascular and non-hypervascular lesions were compared. RESULTS: Visual assessment enabled correct classification of 98% of the lesions to be performed. Quantitatively, we found significant differences between the nTBF values for hypervascular and non-hypervascular lesions (p < 0.001) and provided cut-off values, allowing meningioma and schwannoma to be distinguished from meningioma and adenoma. Significant differences were also found within the hypervascular group, namely, paraganglioma was more hyperperfused than meningioma (p = 0.003) or metastases (p = 0.009). CONCLUSION: The present study demonstrates the high diagnostic performance of pCASL in characterizing skull base lesions by either visual assessment or nTBF quantification. Adding the pCASL sequence to the conventional protocol of skull base assessment can be recommended.

Capecitabine-induced acute toxic leukoencephalopathy.

A 45-year-old woman was treated by Capecitabine (Xeloda®) during 6days for breast cancer with metastatic bone lesions when she presented with nausea, headaches, muscle cramps, dysarthria and swallowing disorders. A stroke was first suspected. Brain CT was normal. MRI showed bilateral and symmetric high signal intensities of deep white matter, corpus callosum and corticospinal tracts on diffusion-weighted imaging and T2 fluid-attenuated inversion recovery (FLAIR) sequence, similar to 5-FU acute leukoencephalopathy. An acute toxic leukoencephalopathy was diagnosed prompting to discontinue capecitabine, which allowed a regression of the symptoms. Though acute toxic leukoencephalopathies with pseudo-stroke presentation have been reported with other chemotherapy agents such as methotrexate or 5-fluorouracil (5-FU), cases of leukoencephalopathy induced by capecitabine are less reported and less well known. This oral precursor of 5-FU is commonly used to treat colorectal, stomach or breast cancers. Neurotoxicity of other 5-FU derivates like cormafur and tergafur have rarely been depicted as well. Although 5-FU-induced leukoencephalopathy is known, the potential toxicity of its precursor should be acknowledged as well. Early detection of chemotherapy-induced toxicity by MRI is crucial as symptoms may be reversible to the condition that chemotherapy is immediately discontinued.

[Neurosarcoidosis: Diagnosis and therapeutic issues]. / Les atteintes neurologiques au cours de la sarcoïdose : diagnostic et traitement.

Neurological localizations of sarcoidosis are heterogeneous and may affect virtually every part of the central or peripheral nervous system. They are often the inaugural manifestation of sarcoidosis. The diagnosis may be difficult due to the lack of extra-neurological localization. Diagnosis may be discussed in the presence of an inflammatory neurological disease, in particular in case of suggestive radiological or biological pattern. Cerebrospinal fluid analysis shows lymphocytic pleiocytosis, often with low glucose level. The diagnosis relies on a clinical, biological and radiological presentation consistent with neurosarcoidosis, the presence of non-caseating granuloma and exclusion of differential diagnoses. Screening for other localizations of sarcoidosis, in particular cardiac disease may be obtained during neurosarcoidosis. The treatment of neurosarcoidosis relies on corticosteroids although immunosuppressive drugs are usually added because of the chronic course of this condition and to limit the side effects of steroids. Treatments and follow-up may be prolonged because of the high rate of relapses.

Cerebral tumor or pseudotumor?

Pseudotumoral lesions are uncommon but important to identity lesions. They can occur during inflammatory diseases (systemic diseases, vasculitis, demyelinating diseases), infectious, and vascular diseases. Also, in a patient with a treated tumor, pseudo-progression and radionecrosis must be differentiated from the tumoral development. Diagnosis can be difficult on an MRI scan, but some MRI aspects in conventional sequences, diffusion, perfusion and spectroscopy can suggest the pseudotumoral origin of a lesion. Imaging must be interpreted according to the context, the clinic and the biology. The presence of associated intracranial lesions can orientate towards a systemic or infectious disease. A T2 hyposignal lesion suggests granulomatosis or histiocytosis, especially if a meningeal or hypothalamic-pituitary involvement is associated. Non-tumoral lesions are generally not hyperperfused. In the absence of a definitive diagnosis, the evolution of these lesions, whether under treatment or spontaneous, is fundamental.

Imaging of the optic chiasm and retrochiasmal visual pathways.

The exploration of the chiasmal and retrochiasmal visual pathways is based on magnetic resonance imaging. A bitemporal hemianopsis suggests a lesion of the optic chiasm while homonymous lateral hemianopsis should lead to a search for a lesion of the retrochiasmal visual pathways. The causes of chiasmal impairment are mainly tumoral. The exploration protocol is based on MRI with T1-weighted sagittal sections, then T2- and T1-weighted coronal sections with and without injection. In case of a retrochiasmal syndrome, the MRI exploration protocol is a function of the type of occurrence of the deficiency and the context.

Imaging findings of intraventricular and ependymal lesions.

Intraventricular and ependymal lesions comprise a wide spectrum of tumoral, cystic, vascular, infectious and inflammatory disorders. With respect to tumoral and cystic diseases, the location, age and CT and MRI patterns are the main factors for diagnosis. The MRI findings of infectious diseases are supported by the clinical history, immune status and laboratory findings. Intracranial associated lesions may be very helpful for the diagnosis of Sturge-Weber, subependymal giant cell astrocytoma and systemic diseases, such as sarcoidosis and histiocytosis. Intraventricular vascular lesions are rare but present typical features on neuroimaging. The aim of this review is to provide a detailed description of these disorders with an emphasis on the key imaging findings and to generate a narrow differential diagnosis. We present a diagnostic approach based on the solid or cystic aspect of the intraventricular focal mass, its origin from the ventricular wall or choroid plexus and its location within the ventricular system. We also propose a differential diagnosis for ependymal dissemination: the ependymal enhancement may be due to ventriculitis from adjacent parenchymal lesions, the ependymal spread of tumors or infectious or inflammatory/systemic diseases.

[Paraganglioma of the cauda equina region: Report of six cases and review of the literature]. / Paragangliomes de la queue de cheval : à propos de six cas et revue de la littérature.

BACKGROUND AND PURPOSE: Paragangliomas of the cauda equina are rare tumors. The standard treatment is surgical resection. Our study aims to compare our clinical, radiological, prognostic data to the literature and to offer management and follow-up recommendations. METHODS: In this retrospective study, six patients with paraganglioma of the cauda equina region were treated. Symptoms included radicular nerve pain and low back pain with occasional sphincter dysfunction and motor deficit. MRI showed well-circumscribed lesions with homogeneous enhancement following gadolinium injection. Treatment involved complete surgical resection of the tumor under electrophysiological control. In addition to the characteristics of the tumor, we assessed operating results as well as postoperative morbidity and follow-up. RESULTS: All patients had complete removal of the tumor, which required in most cases the resection of the carrying root. The intervention allowed a regression of the initial symptoms, with possible postoperative regressive sphincter disorders. Clinical and radiological follow-up (19 months on average), showed no tumor recurrence. CONCLUSIONS: The reference treatment of these tumors is complete surgical resection, usually requiring the sacrifice of the carrying nerve root. Intra-operative nerve roots stimulation is recommended to reduce the risk of motor deficit linked to this radical treatment. A long-term clinical and radiological follow-up is recommended.

[Indications for cerebral MR proton spectroscopy in 2007]. / Spectroscopie par résonance magnétique du proton. Quelles indications neurologiques en 2007?

Magnetic resonance spectroscopy (MRS) is being increasingly performed alongside the more conventional MRI sequences in the exploration of neurological disorders. It is however important to clearly differentiate its clinical applications aiming at improving the differential diagnosis or the prognostic evaluation of the patient, from the research protocols, when MRS can contribute to a better understanding of the pathophysiology of the disease or to the evaluation of new treatments. The most important applications in clinical practice are intracranial space occupying lesions (especially the positive diagnosis of intracranial abscesses and gliomatosis cerebri and the differential diagnosis between edema and tumor infiltration), alcoholic, hepatic, and HIV-related encephalopathies and the exploration of metabolic diseases. Among the research applications, MRS is widely used in multiple sclerosis, ischemia and brain injury, epilepsy and neuro degenerative diseases.

[Brain magnetic resonance spectroscopy]. / Spectroscopie par résonance magnétique cérébrale.

MR spectroscopy (MRS) sequences allow noninvasive exploration of brain metabolism during a MRI examination. Their day-to-day use in a clinical setting has recently been improved by simple programming of sequences and automated quantification of metabolites. However, a few simple rules should be observed in the choice of sequences and the location of the voxels so as to obtain an informative, high-quality examination. The research applications of MR spectroscopy, where use of this examination seeks to better understand the pathophysiology of the disease, must be distinguished from its clinical indications, where MRS provides information that can be used directly in patient management. The most significant of the clinical uses are imaging intracranial tumors (positive and differential diagnosis, extension, treatment follow-up), diffuse brain injury, encephalopathies (especially hepatic and HIV-related), and the diagnosis of metabolic disorders.

[MR spectroscopy of brain tumors]. / Spectroscopie par résonance magnétique des tumeurs cérébrales.

MR spectroscopy (MRS) can complement MRI in the evaluation of intracranial tumors. Before treatment, MRS can contribute to the differential diagnosis between tumor and non tumoral lesion (especially intracranial abscesses), to assess the aggressiveness of a glial tumor or to determine its extension to better delineate the surgical removal or the target volume of radiotherapy. During treatment follow-up, MRS helps differentiate recurrent tumor from radionecrosis or physiological post-surgical contrast enhancement. The current studies are trying to determine if the indications of MRS, alone or in association with other MR sequences can further be extended in the study of brain tumors, in particular the follow-up of lesions undergoing chemo or radiotherapy.

[Changing radiological results, pitfalls and criteria of failure]. / Dynamique des résultats radiologiques, pièges et critères d'échec.

RATIONALE: To evaluate the morphological changes occurring during the Years following radiosurgery in order to better define the cure-failure parameters. MATERIAL AND METHODS: Between July 1992 and January 2002 the otoneurosurgical group of the Timone Hospital in Marseille have operated 1000 vestibular schwannomas. The MR imaging performed before (at diagnosis) during and after radiosurgery (6 months, 1 year, 2 years, 3 years, 5 years, 7 years and 10 years) was carefully studied. Systematically six lenghts measurements were obtained for each lesion. RESULTS: Preoperatively 129 patients were had progressive tumors. At time of radiosurgery, median tumor Volume was 732mm3 (mean: 1346, range: 20-14405). According to the Koos topographical classification, lesions were stage I in 80 patients, stage II in 538 patients, stage III in 322 patients and stage IV in 56 patients. A clear loss of the central enhancement was visible on the postoperative MR control at 6 months and/or 1 Year in 45.5% of patients. In 64% of these patients, this loss of the central contrast enhancement have disappeared. A significant increase of the tumor size was recorded in 15% of the patients. The median increase was 62% (mean: 78%, range: 30-350%). Progression led to salvage surgery (either resection or radiosurgery), in only 3% of the patients. CONCLUSION: The specificity of the morphological changes after radiosurgery, when ignored, can lead to misinterpretation and eventually to inappropriate decisions, dangerous for the patient. The analysis of our results had led us to consider continuous progression after 3 Years as mandatory to retain the diagnosis of failure.

Multimodal magnetic resonance imaging of the central nervous system.

The physiological and biochemical properties of the diseased brain that can be explored with magnetic resonance imaging (MRI) are increasing. Progress in MR-based technology affords a large panel of MRI sequences that explore different phenomena and, thus, provide complementary informations. The diagnostic accuracy of MRI is improved by the combination of all MR modalities. However, this abundance of data requires an efficient multiparametric analysis to fully achieve the goal of the multimodal strategy. We will discuss the potential impact of this advanced MRI analysis in the clinical management and the therapeutical strategies of the most common brain pathologies (intracranial tumors, multiple sclerosis, stroke, epilepsy and dementia). This non-invasive approach is of utmost importance since it already improves the diagnosis and the therapeutic choice in the management of several central nervous system diseases.

MR spectroscopic pulvinar sign in a case of variant Creutzfeldt-Jakob disease.

We report MR spectroscopic findings in a patient hospitalized with biopsy-proven variant Creutzfeldt-Jakob (vCJD) disease. N-acetyl aspartate was markedly decreased in the postero-medial part of the thalami (pulvinar) but was not diminished in the parieto-occipital white matter and cortical grey matter. These observations, which are in accordance with the pathological findings in this disease, suggest that MR spectroscopy, a highly sensitive method for the detection of subtle brain metabolic dysfunction, could be of interest for the diagnosis, prognosis and therapeutic follow-up of vCJD.

Regional metabolite levels of the normal posterior fossa studied by proton chemical shift imaging.

MR spectroscopy of the posterior fossa is pitted with numerous technical difficulties. It is, however, of great clinical interest in the study of the degenerative diseases and tumors of this area. We have developed a method to perform 2D CSI of this area, by using a sagittal slice and a careful positioning of outer volume saturation. We performed this acquisition in 30 healthy volunteers to determine the normal metabolic ratios in five voxels of this area (mesencephalon, pons, medulla oblongata, vermis, cerebellar white matter). The main technical difficulty was magnetic field inhomogeneity in the lower brainstem generated by dental alloys. However, 88% of the voxels were of sufficient quality to be analyzed. The statistically significant regional variations were a higher NAA/Cr ratio in the pons than in the medulla oblongata, higher Cho/Cr in the pons than in the mesencephalon and higher Cho/Cr in the cerebellar white matter than in the vermis. We conclude that 2D CSI of the brainstem, although technically delicate can be performed in most patients.

The amyloid precursor protein interacts with Go heterotrimeric protein within a cell compartment specialized in signal transduction.

The function of the beta-amyloid protein precursor (betaAPP), a transmembrane molecule involved in Alzheimer pathologies, is poorly understood. We recently reported the presence of a fraction of betaAPP in cholesterol and sphingoglycolipid-enriched microdomains (CSEM), a caveolae-like compartment specialized in signal transduction. To investigate whether betaAPP actually interferes with cell signaling, we reexamined the interaction between betaAPP and Go GTPase. In strong contrast with results obtained with reconstituted phospholipid vesicles (Okamoto et al., 1995), we find that incubating total neuronal membranes with 22C11, an antibody that recognizes an N-terminal betaAPP epitope, reduces high-affinity Go GTPase activity. This inhibition is specific of Galphao and is reproduced, in the absence of 22C11, by the addition of the betaAPP C-terminal domain but not by two distinct mutated betaAPP C-terminal domains that do not bind Galphao. This inhibition of Galphao GTPase activity by either 22C11 or wild-type betaAPP cytoplasmic domain suggests that intracellular interactions between betaAPP and Galphao could be regulated by extracellular signals. To verify whether this interaction is preserved in CSEM, we first used biochemical, immunocytochemical, and ultrastructural techniques to unambiguously confirm the colocalization of Galphao and betaAPP in CSEM. We show that inhibition of basal Galphao GTPase activity also occurs within CSEM and correlates with the coimmunoprecipitation of Galphao and betaAPP. The regulation of Galphao GTPase activity by betaAPP in a compartment specialized in signaling may have important consequences for our understanding of the physiopathological functions of betaAPP.