A clinical approach to diagnosis of autoimmune encephalitis

Abstract

Encephalitis is a severe inflammatory disorder of the brain with many possible causes and a complex differential diagnosis. Advances in autoimmune encephalitis research in the past 10 years have led to the identification of new syndromes and biomarkers that have transformed the diagnostic approach to these disorders. However, existing criteria for autoimmune encephalitis are too reliant on antibody testing and response to immunotherapy, which might delay the diagnosis. We reviewed the literature and gathered the experience of a team of experts with the aims of developing a practical, syndrome-based diagnostic approach to autoimmune encephalitis and providing guidelines to navigate through the differential diagnosis. Because autoantibody test results and response to therapy are not available at disease onset, we based the initial diagnostic approach on neurological assessment and conventional tests that are accessible to most clinicians. Through logical differential diagnosis, levels of evidence for autoimmune encephalitis (possible, probable, or definite) are achieved, which can lead to prompt immunotherapy.

Conflict of interest statement

Declaration of interests FG receives royalties from licensing fees to Euroimmun for the use of IgLON5 as a diagnostic test. MJT has received research funding for consultancy work for MedImmune, and a travel grant for Sun Pharma. CGB has given scientific advice to Eisai and UCB; undertaken industry-funded travel with support from Eisai, UCB, Desitin, and Grifols; obtained honoraria for speaking engagements from Eisai, UCB, Desitin, Diamed, Fresenius Medical Care; and received research support from Astellas Pharma, Octapharma, Diamed, and Fresenius Medical Care. CGB is an employee of Krankenhaus Mara, Bielefeld, Germany, which runs a laboratory for the detection of autoantibodies including those described in this paper; external senders are charged for antibody diagnostics. RCD has received research funding from the Star Scientific Foundation and Pfizer Neuroscience and speaker’s honoraria from Biogen Idec and Bristol-Myers Squibb. JMG has received compensation for medical legal consulting and for consulting on a scientific advisory board for Medimmune and Roche; he has received research funding through the University of California, San Francisco, USA, from Quest Diagnostic for work on a dementia care pathway. MG receives grants from Quest Diagnostics and has received personal fees for consultancy work from MedaCorp, Gerson-Lehman Group, Best Doctors, Advance Medical, Inc, and Optio LLC. JH receives royalties from licensing fees to Athena Diagnostics, Euroimmun, and ravo Diagnostika for a patent for the use of CV2/CRMP5 as diagnostic tests. SRI receives royalties from licensing fees to Euroimmun for patents for the use of LGI1, CASPR2, and contactin-2 as autoantibody tests. EL has received speaker’s honoraria and consultancy fees from Grifols, and consultancy fees from Medimmune. FL has received speaker’s honoraria from Grifols, Teva, and Biogen Idec and is employed by University Medical Center Schleswig-Holstein, Kiel, Germany, which offers commercial antibody testing without any personal reimbursements. MR reports that his employers, the University Hospital and Medical University of Innsbruck, Austria, receive payments for antibody assays (NMDA receptor, AQP4, and other autoantibodies) and for AQP4 antibody validation experiments organised by Euroimmun. MRR receives royalties from licensing fees to Euroimmun for a patent for the use of NMDA receptor as an autoantibody test, and from licensing fees to Athena Diagnostics for a patent for the use of Ma2. AS has received compensation for consulting services and speaker honoraria from Bayer-Schering, Merck-Serono, Biogen Idec, Sanofi-Aventis, Teva, and Novartis. AVe reports personal fees from Medimmune. AVi receives royalties from licensing fees to Euroimmun for the use of LGI1 and CASPR2 as diagnostic tests. PW receives royalties for the use of LGI1 and CASPR2 as autoantibody diagnostic tests; is a named inventor on a patent for the use of GABAA receptor as an autoantibody test; and has received speaker honoraria from Biogen Idec and Euroimmun. JD receives royalties from licensing fees to Athena Diagnostics for a patent for the use of Ma2 as an autoantibody test; licensing fees to Euroimmun for patents for the use of NMDA receptor and GABAB receptor as autoantibody tests; licensing fees for the use of DPPX, GABAA receptor, and IgLON5 antibodies as diagnostic tests; and has received a research grant from Euroimmun. RB, SB, TC, IC, CAG, RH, TI, HP, AR-G, KR, and K-PW declare no competing interests. None of the funding sources had any influence in the preparation of this Position Paper.

Copyright © 2016 Elsevier Ltd. All rights reserved.

Figures

Figure 1. Algorithm for the diagnosis of autoimmune encephalitis

AE=autoimmune encephalitis. LE=limbic encephalitis. Abs=antibodies. AQP4=aquaporin 4. MOG=myelin oligodendrocyte glycoprotein. NMDARE=NMDA receptor encephalitis. ADEM=acute disseminated encephalomyelitis. *Although results of autoantibodies are not necessary for a definitive diagnosis of some types of autoimmune encephalitis, their determination is important to further characterise subtypes of limbic encephalitis that have different prognosis, type of treatment, and comorbidities. †See table. ‡Research laboratories can screen for new antibodies (eg, using live neurons). §IgG anti-GluN1 antibodies in the CSF; if only serum is used, confirmatory tests should be included (panel 4). ¶Definitive diagnosis of Bickerstaff’s brainstem encephalitis can be made in the presence of core clinical features (hypersomnolence, ophthalmoplegia, and ataxia) or positive GQ1b antibodies if core symptoms are incomplete.

Figure 2. MRI patterns in autoimmune encephalitis and its mimics

Typical MRI of limbic encephalitis (A) with bilateral abnormalities in the medial temporal lobe on T2-weighted fluid-attenuated inversion recovery imaging; this patient with autopsy-proven limbic encephalitis did not have serum or CSF antineuronal antibodies. Patient with final diagnosis of glioma (B) who presented with unilateral right hippocampal involvement mimicking limbic encephalitis. Typical MRI of acute disseminated encephalomyelitis (C) with bilateral large lesions in the white matter. Multiple lesions involving the corpus callosum in a patient with Susac’s syndrome (D). MRI of a patient with overlapping syndrome (NMDA receptor and myelin oligodendrocyte glycoprotein antibodies; E) showing a right frontal abnormality compatible with demyelination. Diffusion MRI sequence in a patient with AMPA receptor antibody-associated encephalitis (F) mimicking MRI changes seen in patients with Creutzfeldt-Jakob disease. Left side of images=right side of brain.