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.

Collicular Hyperactivation in Patients with COVID-19: A New Finding on Brain MRI and PET/CT.

Hyperactivation of the colliculi has been observed in some patients with coronavirus disease 2019.

Brain MRI of multiple system atrophy of cerebellar type: a prospective study with implications for diagnosis criteria.

AIM: The second consensus statement for the diagnosis of multiple system atrophy type cerebellar (MSA-C) includes pons and middle cerebellar peduncle (MCP) atrophy as MRI features. However, other MRI abnormalities such as MCP hyperintensity, hot cross bun sign (HCB), putaminal hypointensity and hyperintense putaminal rim have been described. OBJECTIVES: To evaluate, in patients with sporadic late-onset cerebellar ataxia (SLOCA), the discriminative value of several MRI features for the diagnosis of MSA-C, to follow their evolution during the course of MSA-C, and to search for correlations between these MRI features and clinical signs. METHODS: Consecutive patients referred for SLOCA underwent comprehensive clinical evaluation and laboratory investigations, brain MRI, DaTscan and a 1-year follow-up. RESULTS: Among 80 patients, 26 had MSA-C, 22 another diagnosis, and 32 no diagnosis at the end of the follow-up. At baseline, MCP hyperintensity and HCB were more frequent in patients finally diagnosed with MSA-C than in other patients with SLOCA (p < 0.0001), and had the highest specificity (98.5%) and positive predictive value (91.7%) for the diagnosis of MSA-C, compared to all other MRI signs. The most relevant MRI sequence regarding HCB sign was the T2-proton density (DP) weighted. All MRI features were more frequent with disease duration. No correlation was found between any MRI feature and neither clinical data, nor dopaminergic neuronal loss (p = 0.5008), except between vermis atrophy and UPDRSIII score. CONCLUSION: MCP hyperintensity and HCB sign should be added into the list of additional features of possible MSA-C. MRI signal abnormalities suggestive of MSA-C should be searched for in suitable sequence.

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.

Prospective study of relevance of 123I-MIBG myocardial scintigraphy and clonidine GH test to distinguish Parkinson's disease and multiple system atrophy.

BACKGROUND: 123I-MIBG myocardial scintigraphy and clonidine growth hormone test (CGH test) may help to distinguish multiple system atrophy (MSA) from Parkinson's disease (PD). Their relevance in the first-stage parkinsonism of uncertain etiology is unknown. METHODS: Patients experiencing parkinsonism of ambiguous etiology were clinically classified into the PD group or the MSA group as initial clinical diagnosis (ICD). Then, CGH test and myocardial scintigraphy were performed. Clinical assessment was repeated throughout the disease course until the final clinical diagnosis (FCD) could be established according to the criteria of PD and MSA, respectively. RESULTS: Twenty-five patients with uncertain diagnosis were included (15 MSA and 10 PD as ICD). At the end of a 6-year follow-up, FCD was MSA in 11/25 patients and PD in 14/25. The CGH test and the scintigraphy showed a sensitivity of 82%, and a specificity of 71 and 93%, respectively, for the diagnosis of MSA. The combination of a normal scintigraphy (i.e., with myocardial MIBG uptake) with genitourinary dysfunction was the most relevant test to diagnose MSA, whereas an abnormal scintigraphy with a levodopa response of > 30% or an abnormal scintigraphy with the absence of OH was the most relevant combinations to diagnose PD. All these combinations had an accuracy superior than 90% and a specificity of 100%. CONCLUSION: Combinations of myocardial scintigraphy with genitourinary dysfunction, levodopa response of > 30%, or orthostatic hypotension could be of interest for the distinction between PD and MSA when the clinical diagnosis remains ambiguous at the first stage of the disease.

Metabolomics approaches in experimental allergic encephalomyelitis.

A myelin basic protein (MBP)-induced experimental allergic encephalomyelitis (EAE) involves paraplegia due to a reversible thoracolumbar spinal cord impairment. The aims of this study were thus to find significant metabolic biomarkers of inflammation and identify the site of inflammation in the central nervous system (CNS) during the acute signs in of the disease using metabolomics. All the EAE samples were associated with higher levels of lactate, ascorbate, glucose and amino acids, and decreased level of N-acetyl-aspartate (NAA) compared to the control group. A decreased NAA level has been particularly shown in lumbar spinal cord in relationship with the clinical signs.

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.

Serum analysis by 1H nuclear magnetic resonance spectroscopy: a new tool for distinguishing neuromyelitis optica from multiple sclerosis.

BACKGROUND: Neuromyelitis optica (NMO) and multiple sclerosis (MS), two inflammatory demyelinating diseases, are characterized by different therapeutic strategies. Currently, the only biological diagnostic tool available to distinguish NMO from MS is the specific serum autoantibody that targets aquaporin 4, but its sensitivity is low. OBJECTIVE: To assess the diagnostic accuracy of metabolomic biomarker profiles in these two neurological conditions, compared to control patients. METHODS: We acquired serum spectra (47 MS, 44 NMO and 42 controls) using proton nuclear magnetic resonance ((1)H-NMR) spectroscopy. We used multivariate pattern recognition analysis to identify disease-specific metabolic profiles. RESULTS: The (1)H-NMR spectroscopic analysis evidenced two metabolites, originating probably from astrocytes, scyllo-inositol and acetate, as promising serum biomarkers of MS and NMO, respectively. In 87.8% of MS patients, scyllo-inositol increased 0.15 to 3-fold, compared to controls and in 74.3% of NMO patients, acetate increased 0.4 to 7-fold, compared to controls. Using these two metabolites simultaneously, we can discriminate MS versus NMO patients (sensitivity, 94.3%; specificity, 90.2%). CONCLUSION: This study demonstrates the potential of (1)H-NMR spectroscopy of serum as a novel, promising analytical tool to discriminate populations of patients affected by NMO or MS.

[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.

Neuroimaging in Cockayne syndrome.

CS is an autosomal recessive multisystem disorder, which is mainly characterized by neurologic and sensory impairment, cachectic dwarfism, and photosensitivity. We describe the neuroimaging features (MR imaging, ¹H-MR spectroscopy, and CT) in the various clinical subtypes of CS from a cohort of genetically and biochemically proved cases. Hypomyelination, calcifications, and brain atrophy were the main imaging features. Calcifications were typically found in the putamen and less often in the cortex and dentate nuclei. Severe progressive atrophy was seen in the supratentorial white matter, the cerebellum, the corpus callosum, and the brain stem. Patients with early-onset disease displayed more severe hypomyelination and prominent calcifications in the sulcal depth of the cerebral cortex, but atrophy was less severe in late-onset patients. On proton MR spectroscopy, lactate was detected and Cho and NAA values were decreased. These combined neuroradiologic findings can help in the differential diagnosis of CS, distinguishing it from other leukoencephalopathies and/or cerebral calcifications in childhood.

Usefulness of functional MRI associated with PET scan and evoked potentials in the evaluation of brain functions after severe brain injury: preliminary results.

OBJECTIVE: To evaluate the feasability and the potential usefulness of functional MRI (fMRI) for the evaluation of brain functions after severe brain injury, when compared to a multimodal approach (evoked potentials [EP] and Positron Emission Tomography [PET] examinations). MATERIAL AND METHODS: Seven patients (mean age: 49 years [23-73], three males, four females) presenting with coma after acute severe brain injuries underwent fMRI (auditive, visual, somesthesic), (18)F-FDG PET and EP (auditive, visual, somesthesic) within a 3-day period of time in a mean of 120 days after initial brain injury. fMRI activations in somesthesic, visual and auditive cortical areas were compared to EP (28 possible comparisons) and to the metabolic activity on PET examination in the same anatomical areas (21 possible comparisons). RESULTS: In case of availability, results were concordant between fMRI and PET in 10 comparisons but not in one, and between fMRI and EP in 11 comparisons but not in four. CONCLUSIONS: In many patients, there is a good concordance between fMRI and brain functions suggested by EP and metabolic activity demonstrated with PET. In few others, fMRI can be integrated in the early evaluation of brain functions to further augment our capacity for a proper evaluation of brain functions in critically ill patients.

Effects of lorazepam on brain activity pattern during an anxiety symptom provocation challenge.

Human models of anxiety are useful to develop new effective anxiolytics. The objective of this study was to use functional magnetic resonance imaging (fMRI) to test the hypothesis that a single dose of lorazepam modifies brain activation during an anxiety challenge. Eighteen healthy male subjects underwent fMRI associated with a challenge based on the anticipation of aversive electrical stimulations after pretreatment, either with placebo or with 1.0 mg of oral lorazepam. Anxiety was rated before fMRI and after, referring to the threat condition periods, using State Trait Anxiety Inventory (STAI) and Hamilton scales. The conditioning procedure induced anxiety, as indicated by clinical rating score changes. Lorazepam did not modify anxiety rating as compared to placebo. Lorazepam reduced cerebral activity in superior frontal gyrus, anterior insula/inferior frontal gyrus and cingulate gyrus. The current finding provides the first evidence of the modulatory effects of an established anxiolytic agent on brain activation related to anticipatory anxiety.

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.

Foreign accent syndrome as a first sign of multiple sclerosis.

BACKGROUND: Foreign accent syndrome (FAS) consists of a speech rhythm disorder different from dysarthia or aphasia. It is unusually met in multiple sclerosis (MS). OBJECTIVE: We report a case of FAS as an initial symptom of a MS. METHODS: A right-handed French woman developed an isolated German foreign accent. Brain magnetic resonance imaging (MRI), SPECT and analysis of CSF were performed. RESULTS: Brain MRI revealed a large hypersignal on T2-weighted images in the left prerolandic white matter. Single photon emission computed tomography showed a right prerolandic hypoperfusion. Unmatched oligoclonal bands in cerebrospinal fluid and occurrence of new abnormal hypersignals on the following MRI led us to diagnose MS. CONCLUSION: FAS may be the first symptom of MS. It could result from extensive disturbances of brain function involving the right hemisphere.

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.