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      Abnormal brain metabolism on FDG-PET/CT is a common early finding in autoimmune encephalitis

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          Abstract

          Objective:

          To compare the rate of abnormal brain metabolism by FDG-PET/CT to other paraclinical findings and to describe brain metabolism patterns in autoimmune encephalitis (AE).

          Methods:

          A retrospective review of clinical data and initial dedicated brain FDG-PET/CT studies for neurology inpatients with AE, per consensus criteria, treated at a single tertiary center over 123 months. Z-score maps of FDG-PET/CT were made using 3-dimensional stereotactic surface projections with comparison to age group–matched controls. Brain region mean Z-scores with magnitudes ≥2.00 were interpreted as significant. Comparisons were made to rates of abnormal initial brain MRI, abnormal initial EEG, and presence of intrathecal inflammation.

          Results:

          Sixty-one patients with AE (32 seropositive) underwent brain FDG-PET/CT at median 4 weeks of symptoms (interquartile range [IQR] 9 weeks) and median 4 days from MRI (IQR 8.5 days). FDG-PET/CT was abnormal in 52 (85%) patients, with 42 (69%) demonstrating only hypometabolism. Isolated hypermetabolism was demonstrated in 2 (3%) patients. Both hypermetabolic and hypometabolic brain regions were noted in 8 (13%) patients. Nine (15%) patients had normal FDG-PET/CT studies. CSF inflammation was evident in 34/55 (62%) patients, whereas initial EEG (17/56, 30%) and MRI (23/57, 40%) were abnormal in fewer. Detection of 2 or more of these paraclinical findings was in weak agreement with abnormal brain FDG-PET/CT (κ = 0.16, p = 0.02).

          Conclusions:

          FDG-PET/CT was more often abnormal than initial EEG, MRI, and CSF studies in neurology inpatients with AE, with brain region hypometabolism the most frequently observed.

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          Most cited references26

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          A diagnostic approach in Alzheimer's disease using three-dimensional stereotactic surface projections of fluorine-18-FDG PET.

          To improve the diagnostic performance of PET as an aid in evaluating patients suspected of having Alzheimer's disease, we developed a fully automated method which generates comprehensive image presentations and objective diagnostic indices. Fluorine-18-fluorodeoxyglucose PET image sets were collected from 37 patients with probable Alzheimer's disease (including questionable and mild dementia), 22 normal subjects and 5 patients with cerebrovascular disease. Following stereotactic anatomic standardization, metabolic activity on an individual's PET image set was extracted to a set of predefined surface pixels (three-dimensional stereotactic surface projection, 3D-SSP), which was used in the subsequent analysis. A normal database was created by averaging extracted datasets of the normal subjects. Patients' datasets were compared individually with the normal database by calculating a Z-score on a pixel-by-pixel basis and were displayed in 3D-SSP views for visual inspections. Diagnostic indices were then generated based on averaged Z-scores for the association cortices. Patterns and severities of metabolic reduction in patients with probable Alzheimer's disease were seen in the standard 3D-SSP views of extracted raw data and statistical Z-scores. When discriminating patients with probable Alzheimer's disease from normal subjects, diagnostic indices of the parietal association cortex and unilaterally averaged parietal-temporal-frontal cortex showed sensitivities of 95% and 97%, respectively, with a specificity of 100%. Neither index yielded false-positive results for cerebrovascular disease. 3D-SSP enables quantitative data extraction and reliable localization of metabolic abnormalities by means of stereotactic coordinates. The proposed method is a promising approach for interpreting functional brain PET scans.
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            FDG-PET improves accuracy in distinguishing frontotemporal dementia and Alzheimer's disease.

            Distinguishing Alzheimer's disease (AD) and frontotemporal dementia (FTD) currently relies on a clinical history and examination, but positron emission tomography with [(18)F] fluorodeoxyglucose (FDG-PET) shows different patterns of hypometabolism in these disorders that might aid differential diagnosis. Six dementia experts with variable FDG-PET experience made independent, forced choice, diagnostic decisions in 45 patients with pathologically confirmed AD (n = 31) or FTD (n = 14) using five separate methods: (1) review of clinical summaries, (2) a diagnostic checklist alone, (3) summary and checklist, (4) transaxial FDG-PET scans and (5) FDG-PET stereotactic surface projection (SSP) metabolic and statistical maps. In addition, we evaluated the effect of the sequential review of a clinical summary followed by SSP. Visual interpretation of SSP images was superior to clinical assessment and had the best inter-rater reliability (mean kappa = 0.78) and diagnostic accuracy (89.6%). It also had the highest specificity (97.6%) and sensitivity (86%), and positive likelihood ratio for FTD (36.5). The addition of FDG-PET to clinical summaries increased diagnostic accuracy and confidence for both AD and FTD. It was particularly helpful when raters were uncertain in their clinical diagnosis. Visual interpretation of FDG-PET after brief training is more reliable and accurate in distinguishing FTD from AD than clinical methods alone. FDG-PET adds important information that appropriately increases diagnostic confidence, even among experienced dementia specialists.
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              Treatment-responsive limbic encephalitis identified by neuropil antibodies: MRI and PET correlates.

              We report seven patients, six from a single institution, who developed subacute limbic encephalitis initially considered of uncertain aetiology. Four patients presented with symptoms of hippocampal dysfunction (i.e. severe short-term memory loss) and three with extensive limbic dysfunction (i.e. confusion, seizures and suspected psychosis). Brain MRI and [(18)F]fluorodeoxyglucose (FDG)-PET complemented each other but did not overlap in 50% of the patients. Combining both tests, all patients had temporal lobe abnormalities, five with additional areas involved. In one patient, FDG hyperactivity in the brainstem that was normal on MRI correlated with central hypoventilation; in another case, hyperactivity in the cerebellum anticipated ataxia. All patients had abnormal CSF: six pleocytosis, six had increased protein concentration, and three of five examined had oligoclonal bands. A tumour was identified and removed in four patients (mediastinal teratoma, thymoma, thymic carcinoma and thyroid cancer) and not treated in one (ovarian teratoma). An immunohistochemical technique that facilitates the detection of antibodies to cell surface or synaptic proteins demonstrated that six patients had antibodies to the neuropil of hippocampus or cerebellum, and one to intraneuronal antigens. Only one of the neuropil antibodies corresponded to voltage-gated potassium channel (VGKC) antibodies; the other five (two with identical specificity) reacted with antigens concentrated in areas of high dendritic density or synaptic-enriched regions of the hippocampus or cerebellum. Preliminary characterization of these antigens indicates that they are diverse and expressed on the neuronal cell membrane and dendrites; they do not co-localize with VGKCs, but partially co-localize with spinophilin. A target autoantigen in one of the patients co-localizes with a cell surface protein involved in hippocampal dendritic development. All patients except the one with antibodies to intracellular antigens had dramatic clinical and neuroimaging responses to immunotherapy or tumour resection; two patients had neurological relapse and improved with immunotherapy. Overall, the phenotype associated with the novel neuropil antibodies includes dominant behavioural and psychiatric symptoms and seizures that often interfere with the evaluation of cognition and memory, and brain MRI or FDG-PET abnormalities less frequently restricted to the medial temporal lobes than in patients with classical paraneoplastic or VGKC antibodies. When compared with patients with VGKC antibodies, patients with these novel antibodies are more likely to have CSF inflammatory abnormalities and systemic tumours (teratoma and thymoma), and they do not develop SIADH-like hyponatraemia. Although most autoantigens await characterization, all share intense expression by the neuropil of hippocampus, with patterns of immunolabelling characteristic enough to suggest the diagnosis of these disorders and predict response to treatment.
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                Author and article information

                Contributors
                Journal
                Neurol Neuroimmunol Neuroinflamm
                Neurol Neuroimmunol Neuroinflamm
                nnn
                NEURIMMINFL
                Neurology® Neuroimmunology & Neuroinflammation
                Lippincott Williams & Wilkins (Hagerstown, MD )
                2332-7812
                11 May 2017
                July 2017
                11 May 2017
                : 4
                : 4
                : e352
                Affiliations
                From the Department of Neurology (J.C.P., A.N., J.C., A.V.), Johns Hopkins Encephalitis Center, Department of Neurology (J.C.P.), Johns Hopkins Center for Refractory Status Epilepticus and Neuroinflammation, and Russell H. Morgan Department of Radiology and Radiological Sciences (L.S., K.M.J., E.Z., M.S.J.), Johns Hopkins University School of Medicine, Baltimore, MD.
                Author notes
                Correspondence to Dr. Probasco: jprobas1@ 123456jhmi.edu

                Funding information and disclosures are provided at the end of the editorial. Go to Neurology.org/nn for full disclosure forms. The Article Processing Charge was funded by the authors.

                Article
                NEURIMMINFL2016011593
                10.1212/NXI.0000000000000352
                5442608
                28567435
                73cc57a2-885a-4ebb-b144-7cb3e32567d2
                Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

                History
                : 23 January 2017
                : 27 March 2017
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