Unravelling the etiology of sporadic late-onset cerebellar ataxia in a cohort of 205 patients: a prospective study.

BACKGROUND: Despite recent progress in the field of genetics, sporadic late-onset (> 40 years) cerebellar ataxia (SLOCA) etiology remains frequently elusive, while the optimal diagnostic workup still needs to be determined. We aimed to comprehensively describe the causes of SLOCA and to discuss the relevance of the investigations. METHODS: We included 205 consecutive patients with SLOCA seen in our referral center. Patients were prospectively investigated using exhaustive clinical assessment, biochemical, genetic, electrophysiological, and imaging explorations. RESULTS: We established a diagnosis in 135 (66%) patients and reported 26 different causes for SLOCA, the most frequent being multiple system atrophy cerebellar type (MSA-C) (41%). Fifty-one patients (25%) had various causes of SLOCA including immune-mediated diseases such as multiple sclerosis or anti-GAD antibody-mediated ataxia; and other causes, such as alcoholic cerebellar degeneration, superficial siderosis, or Creutzfeldt-Jakob disease. We also identified 11 genetic causes in 20 patients, including SPG7 (n = 4), RFC1-associated CANVAS (n = 3), SLC20A2 (n = 3), very-late-onset Friedreich's ataxia (n = 2), FXTAS (n = 2), SCA3 (n = 1), SCA17 (n = 1), DRPLA (n = 1), MYORG (n = 1), MELAS (n = 1), and a mitochondriopathy (n = 1) that were less severe than MSA-C (p < 0.001). Remaining patients (34%) had idiopathic late-onset cerebellar ataxia which was less severe than MSA-C (p < 0.01). CONCLUSION: Our prospective study provides an exhaustive picture of the etiology of SLOCA and clues regarding yield of investigations and diagnostic workup. Based on our observations, we established a diagnostic algorithm for SLOCA.

Diagnostic value of fusion of metabolic and structural images for stereotactic biopsy of brain tumors without enhancement after contrast medium injection.

BACKGROUND: The heterogeneous nature of glioma makes it difficult to select a target for stereotactic biopsy that will be representative of grade severity on non-contrast-enhanced lesion imaging. The objective of this study was to evaluate the benefit of fusion of metabolic images (PET 18F-DOPA) with magnetic resonance imaging (MRI) morphological images for cerebral biopsy under stereotactic conditions of glioma without contrast enhancement. PATIENTS AND METHODS: This single-center prospective observational study conducted between January 2016 and April 2018 included 20 consecutive patients (mean age: 45±19.5 years; range, 9-80 years) who underwent cerebral biopsy for a tumor without MRI enhancement but with hypermetabolism on 18F-FDOPA PET (positron emission tomography). Standard 18F-FDOPA uptake value (SUVmax) was determined for diagnosis of high-grade glioma, with comparison to histomolecular results. RESULTS: Histological diagnosis was made in all patients (100%). Samples from hypermetabolism areas revealed high-grade glial tumor in 16 patients (80%). For a SUVmax threshold of 1.75, sensitivity was 81.2%, specificity 50%, PPV 86.7% and VPN 40% for diagnosis of high-grade glioma. No significant association between SUVmax and histomolecular mutation was found. CONCLUSION: 18F-FDOPA metabolic imaging is an aid in choosing the target to be biopsied under stereotactic conditions in tumors without MR enhancement. Nevertheless, despite good sensitivity, 18F-FDOPA PET is insufficient for definitive diagnosis of high-grade tumor.

Deciphering the causes of sporadic late-onset cerebellar ataxias: a prospective study with implications for diagnostic work.

The management of sporadic late-onset cerebellar ataxias represents a very heterogeneous group of patients and remains a challenge for neurologist in clinical practice. We aimed at describing the different causes of sporadic late-onset cerebellar ataxias that were diagnosed following standardized, exhaustive investigations and the population characteristics according to the aetiologies as well as at evaluating the relevance of these investigations. All patients consecutively referred to our centre due to sporadic, progressive cerebellar ataxia occurring after 40 years of age were included in the prospective, observational study. 80 patients were included over a 2 year period. A diagnosis was established for 52 patients (65%) corresponding to 18 distinct causes, the most frequent being cerebellar variant of multiple system atrophy (n = 29). The second most frequent cause was inherited diseases (including spinocerebellar ataxias, late-onset Friedreich's disease, SLC20A2 mutations, FXTAS, MELAS, and other mitochondrial diseases) (n = 9), followed by immune-mediated or other acquired causes. The group of patient without diagnosis showed a slower worsening of ataxia (p < 0.05) than patients with multiple system atrophy. Patients with later age at onset experienced faster progression of ataxia (p = 0.001) and more frequently parkinsonism (p < 0.05) than patients with earlier onset. Brain MRI, DaT scan, genetic analysis and to some extent muscle biopsy, thoracic-abdominal-pelvic tomodensitometry, and cerebrospinal fluid analysis were the most relevant investigations to explore sporadic late-onset cerebellar ataxia. Sporadic late-onset cerebellar ataxias should be exhaustively investigated to identify the underlying causes that are numerous, including inherited causes, but dominated by multiple system atrophy.

Metabolomics approaches in pancreatic adenocarcinoma: tumor metabolism profiling predicts clinical outcome of patients.

BACKGROUND: Pancreatic adenocarcinomas (PAs) have very poor prognoses even when surgery is possible. Currently, there are no tissular biomarkers to predict long-term survival in patients with PA. The aims of this study were to (1) describe the metabolome of pancreatic parenchyma (PP) and PA, (2) determine the impact of neoadjuvant chemotherapy on PP and PA, and (3) find tissue metabolic biomarkers associated with long-term survivors, using metabolomics analysis. METHODS: 1H high-resolution magic angle spinning (HRMAS) nuclear magnetic resonance (NMR) spectroscopy using intact tissues was applied to analyze metabolites in PP tissue samples (n = 17) and intact tumor samples (n = 106), obtained from 106 patients undergoing surgical resection for PA. RESULTS: An orthogonal partial least square-discriminant analysis (OPLS-DA) showed a clear distinction between PP and PA. Higher concentrations of myo-inositol and glycerol were shown in PP, whereas higher levels of glucose, ascorbate, ethanolamine, lactate, and taurine were revealed in PA. Among those metabolites, one of them was particularly obvious in the distinction between long-term and short-term survivors. A high ethanolamine level was associated with worse survival. The impact of neoadjuvant chemotherapy was higher on PA than on PP. CONCLUSIONS: This study shows that HRMAS NMR spectroscopy using intact tissue provides important and solid information in the characterization of PA. Metabolomics profiling can also predict long-term survival: the assessment of ethanolamine concentration can be clinically relevant as a single metabolic biomarker. This information can be obtained in 20 min, during surgery, to distinguish long-term from short-term survival.

[Morpho-functional imaging in a patient with hyperparathyroidism and multifocal maxillary brown tumor]. / Imagerie morphologique et fonctionnelle des tumeurs brunes. À propos d'un cas de localisation maxillo-mandibulaire.

INTRODUCTION: Brown tumors are uncommon osteolytic lesions directly related to the increased osteoclastic activity due to hyperparathyroidism. CASE REPORT: A 37-year-old woman presented with hypercalcemia related to primary hyperparathyroidism. Multiple and bilateral maxillary osteolytic lesions showing intense fluorodesoxyglucose (FDG) uptake were noted in a positron emission tomography computed tomography (PET-CT). Diagnosis of maxillary brown tumors was discussed and confirmed by both orthopantomogram and magnetic resonance imaging. Left inferior parathyroid adenoma was detected by both cervical ultrasonography and parathyroid scintigraphy, and then surgically treated with consequent improvement of hyperparathyroidism. CONCLUSION: Our case emphasizes the necessity of a multidisciplinary diagnostic approach to optimize the interpretation of the available imaging, especially in unusual and unrecognized pathology as brown tumors.

Ultrafast in vivo microwave irradiation for enhanced metabolic stability of brain biopsy samples during HRMAS NMR analysis.

High resolution magic-angle spinning (HRMAS) NMR spectroscopy is a well established technique for ex vivo metabolite investigations but experimental factors such as ischemic delay or mechanical stress due to continuous spinning deserve further investigations. Cortical brain samples from rats that underwent ultrafast in vivo microwave irradiation (MWp group) were compared to similar samples that underwent standard nitrogen freezing with and without exposure to domestic microwaves (FN and FN+MWd groups). One dimensional (1)H HRMAS NMR spectra were acquired and 16 metabolites of interest were quantified. Within each group 3 samples underwent long lasting acquisition (up to 15 h). Statistically significant differences in metabolite concentrations were observed between groups for metabolites associated to post mortem biochemical changes and/or anaerobic glycolysis including several neurotransmitters. Spectral assessment over time showed a drastic reduction of biochemical variations in both MW groups. Only 2/16 metabolites exhibited significant signal variations after 15 h of continuous spinning and acquisition in the MWp group. This number increased to 10 in the FN group. We confirmed limited anaerobic metabolism and post mortem degradation after ultra fast in vivo MW irradiation. Furthermore, spectra obtained after MWp and MWd irradiation exhibited an extremely stable spectral pattern over extended periods of continuous acquisition.

Metabolomic Characterization of Ovarian Epithelial Carcinomas by HRMAS-NMR Spectroscopy.

Objectives. The objectives of the present study are to determine if a metabolomic study by HRMAS-NMR can (i) discriminate between different histological types of epithelial ovarian carcinomas and healthy ovarian tissue, (ii) generate statistical models capable of classifying borderline tumors and (iii) establish a potential relationship with patient's survival or response to chemotherapy. Methods. 36 human epithelial ovarian tumor biopsies and 3 healthy ovarian tissues were studied using (1)H HRMAS NMR spectroscopy and multivariate statistical analysis. Results. The results presented in this study demonstrate that the three histological types of epithelial ovarian carcinomas present an effective metabolic pattern difference. Furthermore, a metabolic signature specific of serous (N-acetyl-aspartate) and mucinous (N-acetyl-lysine) carcinomas was found. The statistical models generated in this study are able to predict borderline tumors characterized by an intermediate metabolic pattern similar to the normal ovarian tissue. Finally and importantly, the statistical model of serous carcinomas provided good predictions of both patient's survival rates and the patient's response to chemotherapy. Conclusions. Despite the small number of samples used in this study, the results indicate that metabolomic analysis of intact tissues by HRMAS-NMR is a promising technique which might be applicable to the therapeutic management of patients.

Acute limbic encephalitis and glutamic acid decarboxylase antibodies: a reality?

Limbic encephalitis (LE) associated with glutamic acid decarboxylase antibodies (GAD-Ab) is rare. We describe a 30-year-old male with acute LE and GAD-Ab, with follow-up during 2 years of cognitive status including verbal episodic memory, number of seizures recorded by high-resolution video-EEG, brain MRI, 2-[18F]-fluoro-2-deoxyglucose PET and GAD-Ab titres. Treatment with corticosteroids, IV immunoglobulins, immunosuppressors and antiepileptic drugs resulted in improved memory status, disappearance of seizures and decreased GAD-Ab titres. Review of the other cases of literature and this case is in favour of the existence of autoimmune LE associated with GAD-Ab and supports the link between memory, temporal seizures and possibly GAD-Ab titres.

SPM analysis of ictal-interictal SPECT in mesial temporal lobe epilepsy: relationships between ictal semiology and perfusion changes.

A combination of temporo-limbic hyperperfusion and extratemporal hypoperfusion was observed during complex partial seizures (CPS) in temporal lobe epilepsy (TLE). To investigate the clinical correlate of perfusion changes in TLE, we analyzed focal seizures of increasing severity using voxel-based analysis of ictal SPECT. We selected 26 pre-operative pairs of ictal-interictal SPECTs from adult mesial TLE patients, seizure-free after surgery. Ictal SPECTs were classified in three groups: motionless seizures (group ML, n=8), seizures with motor automatisms (MA) without dystonic posturing (DP) (group MA, n=8), and seizures with DP with or without MA (DP, n=10). Patients of group ML had simple partial seizures (SPS), while others had CPS. Groups of ictal-interictal SPECT were compared to a control group using statistical parametric mapping (SPM). In ML group, SPM analysis failed to show significant changes. Hyperperfusion involved the anteromesial temporal region in MA group, and also the insula, posterior putamen and thalamus in DP group. Hypoperfusion was restricted to the posterior cingulate and prefrontal regions in MA group, and involved more widespread associative anterior and posterior regions in DP group. Temporal lobe seizures with DP show the most complex pattern of combined hyper-hypoperfusion, possibly related both to a larger spread and the recruitment of more powerful inhibitory processes.

Toward improved grading of malignancy in oligodendrogliomas using metabolomics.

In spite of having been the object of considerable attention, the histopathological grading of oligodendrogliomas is still controversial. The determination of reliable biomarkers capable of improving the malignancy grading remains an essential step in working toward better therapeutic management of patients. Therefore the metabolome of 34 human brain biopsies, histopathologically classified as low-grade (LGO, N = 10) and high-grade (HGO, N = 24) oligodendrogliomas, was studied using high-resolution magic angle spinning nuclear magnetic resonance spectroscopy (HRMAS NMR) and multivariate statistical analysis. The classification model obtained afforded a clear distinction between LGOs and HGOs and provided some useful insights into the different metabolic pathways that underlie malignancy grading. The analysis of the most discriminant metabolites in the model revealed the presence of tumoral hypoxia in HGOs. The statistical model was then used to study biopsy samples that were classified as intermediate oligodendrogliomas (N = 6) and glioblastomas (GBMs) (N = 30) by histopathology. The results revealed a gradient of tumoral hypoxia increasing in the following direction: LGOs, intermediate oligodendrogliomas, HGOs, and GBMs. Moreover upon analysis of the clinical evolution of the patients, the metabolic classification seems to provide a closer correlation with the actual patient evolution than the histopathological analysis.

[Epileptogenic and non-epileptogenic zones: blood flow studies of temporo-limbic seizures]. / Zones épileptogènes et non-épileptogènes: imagerie de perfusion des crises temporo-limbiques.

To assess the contribution of ictal SPECT to the definition of the epileptogenic zone (EZ) prior to surgery in focal drug-resistant epilepsies, we investigated the effect of the timing of injection and seizure semiology on patterns of perfusion and cerebral blood flow changes (CBF) beyond the EZ. In the rat model of amygdala-kindled seizures, we measured CBF changes with the quantitative [(14)C]-iodoantipyrine autoradiographic method during secondary generalized (SGS, n=26 fully-kindled rats) and focal seizures (FS, n=19 partially kindled rats), according to sequential timing of injection with respect to seizure onset. During SGS, the correct lateralization and rough localization of the focus within limbic structures was only possible at the early ictal and post-ictal times, in between we observed widespread rCBF increases. The switch from hyper to hypoperfusion occurred at the time of late ictal injection. The accurate localization of the EZ was obtained in the study of the more subtle FS (stage 0). At stage 1 of the kindling, there was already a remote widespread spreading of hyperperfusion. In patients surgically cured from a mesio-temporal lobe epilepsy (mean post-operative follow-up: 66 months), we retrospectively studied 26 pairs of ictal and interictal pre-operative SPECTs, classified in 3 groups according to the progression of ictal semiology. Using visual analysis of subtracted SPECTs (SISCOM) and group comparisons with a control group (using SPM), we observed more widespread combined hyper and hypoperfusion with the increasing complexity of seizures. In simple partial seizures, the SISCOM analysis allowed a correct localization of the focus in 4/8 patients, whereas the SPM analysis failed to detect significant changes, due to individual variation, spatial normalization and small magnitude of CBF changes. In complex partial seizures with automatisms, SISCOM and SPM analysis showed antero-mesial temporal hyperperfusion (overlapping the EZ), extending to the insula, basal ganglia, and thalamus in the group of patients having dystonic posturing (DP group) in addition to automatisms. Ictal hypoperfusion involved pre-frontal and parietal regions, the anterior and posterior cingulate gyri, to a greater extent in the DP group. In both human and animals studies, we observed a correlation between the extent of composite patterns of hyper/hypoperfusion and the severity of seizures, and the recruitment of remote sub-cortical structures. Hypoperfused areas belong to neural networks involved in perceptual decision making and motor planning, whose transient disruption could support purposeless actions, i.e. motor automatisms.

Contribution of SISCOM imaging in the presurgical evaluation of temporal lobe epilepsy related to dysembryoplastic neuroepithelial tumors.

PURPOSE: Dysembryoplastic neuroepithelial tumors (DNTs) are a group of glioneuronal supratentorial and intracortical lesions often associated with the early onset of intractable and crippling partial seizures. They are characterized by their location, multinodular architecture, and heterogeneous cell composition, with a specific glioneuronal element in the specific form. Foci of cortical dysplasia may be associated with the tumoral lesion, and identifying the presence and the extent of cortical dysplasia is not always easy on magnetic resonance images (MRIs). The purpose of this article is to evaluate, retrospectively, the usefulness of ictal single-photon emission computed tomography (SPECT) imaging to assess the presence and the extent of cortical dysplasia associated with DNTs in nine patients with intractable temporal lobe epilepsy related to histopathologically confirmed DNTs. METHODS: The results of the subtraction of ictal and interictal SPECT coregistered to MRI (SISCOM) were compared with the results of the examinations of pathological material after surgery. RESULTS: SISCOM showed a strongly hyperperfused area corresponding anatomically to electroclinical abnormalities and to the location of DNTs on MRI. A circumscribed hyperperfusion was present in DNTs without cortical dysplasia, limited to the location of the tumor on MRI. In cases of associated cortical dysplasia, a widespread hyperperfusion including areas corresponding to normal perilesional regions on MRI was found. CONCLUSIONS: SISCOM, used among presurgical investigations, contributes to detecting cortical dysplasia associated with DNTs. Concordance between the symptomatogenic zone (defined from the medical history and electroclinical data), MRI scans, SISCOM pattern, and complete resection of the epileptic zone was predictive of a good postsurgical outcome.

Language functional neuro-imaging changes following focal left thalamic infarction.

The involvement of the left thalamus in language function has been largely demonstrated through the effects of thalamic lesion and/or stimulation upon language. However, the pathophysiological mechanisms underlying thalamic aphasias remain a matter of debate. We report here on changes in the pattern of brain activity in auditory word processing, verb generation and visual lexical decision in a patient who sustained left thalamic infarct following the surgery of intractable mesio-temporal epilepsy with left hippocampal sclerosis. To some extent, our findings exemplify the way the left thalamus brings on line the cortical networks involved in language processing, suggested in the term 'selective engagement'.

Spinal meningiomas.

Between the years of 1970-1982 29 spinal meningioma cases were operated on; 22 cases (76%) were female and 7 (24%) were male. The youngest patient was 16, and the oldest was 68 years old. On neurological examination, patients had neurological deficits in varying degrees. Diagnosis were done by myelography in all cases. Laminectomy was performed in all cases. 34.4% of cases were situated in cervical region and 65.6% were in thoracic region. 14% of the tumours were located extradurally and 68% were intradural. Multiple spinal meningioma was seen in only one case. One case died after operation; the mortality rate is 4%. 22 cases came for follow-up examination, 86.5% of them were in excellent or good condition. Only three cases showed no improvement.

Peripheral nervous system involvement in Behçet's disease. Case report and review of the literature.

Central nervous system complication of Behçet's disease are well recognized. However, peripheral nervous system involvement has been rarely observed. A case of Behçet's disease with prominent peripheral nervous system involvement is reported in this article. The results of clinical, electromyographic, immunologic and electron-microscopic findings of a nerve biopsy are presented and discussed in the light of the literature.

[Primary carcinoma of the choroid plexus. 2 case reports and review of the literature]. / Carcinome primitif du plexus choroïde. Présentation de deux cas et revue de la littérature.

Primary Carcinomas of Choroid Plexus are seen rarely. In previous literature there were 37 cases which were reported according to Lewis and Russel-Rubinstein malignancy criterias. In this article, we describe 5 years old boy and 1.5 year old girl who suffered from cerebellar ataxia and intracranial pressure increase syndrome. In case 1, the tumor of the fourth ventricle was diagnosed by brachial angiography and ventriculography. In case 2, the diagnosis was established by CT scan. In case 1, the patient died during the postoperative course. In case 2, the postoperative time was unremarkable. A radiotherapy of 3 000 rads was applied to the posterior fossa. One year later, the patient had only mild ataxia.

[Intracranial ependymomas. Study of 81 cases and comparison with the literature]. / Les épendymomes intracraniens. Etude de 81 cas et comparaison avec la littérature.

For ten-years of period, between 1973-1982, 81 cases with intracranial ependymoma have been operated in H.U.T.F. Neurosurgery Department. Supratentorial localisation have been found in 24 cases (30%), and infratentorial in 57 (70%). 80% of the patients in supratentorial group and 91% in infratentorial group were under the age 20. In supratentorial group 79% were in paraventricular localisation, and 21% were intraventricular. In infratentorial group 70% of the cases were localised within the IV. ventricle, 20% in province of the tentorial roof, 5% in the lateral recessus and 5% into cerebellum. The 40 patients who were followed up were rated according to the localisation and the grades of the tumors, the type of the surgical intervention and chemotherapy with respect to the postoperative survival. As a result only the total resection of the tumor was found to be significant.