Elsevier

The Lancet Neurology

Volume 15, Issue 4, April 2016, Pages 391-404
The Lancet Neurology

Position Paper
A clinical approach to diagnosis of autoimmune encephalitis

https://doi.org/10.1016/S1474-4422(15)00401-9Get rights and content

Summary

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.

Introduction

Acute encephalitis is a debilitating neurological disorder that develops as a rapidly progressive encephalopathy (usually in less than 6 weeks) caused by brain inflammation.1 The estimated incidence of encephalitis in high-income countries is about 5–10 per 100 000 inhabitants per year; encephalitis affects patients of all ages and represents a significant burden to patients, families, and society.2, 3

Because the most frequently recognised causes of encephalitis are infectious, existing diagnostic criteria and consensus guidelines for encephalitis assume an infectious origin.1, 4, 5, 6 However, in the past 10 years an increasing number of non-infectious, mostly autoimmune, encephalitis cases have been identified and some of them do not meet existing criteria.7 These newly identified forms of autoimmune encephalitis might be associated with antibodies against neuronal cell-surface or synaptic proteins (table)8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 and can develop with core symptoms resembling infectious encephalitis, and also with neurological and psychiatric manifestations without fever or CSF pleocytosis.7 To improve the recognition of these disorders, in this Position Paper, we aim to provide a practical clinical approach to diagnosis that should be accessible to most physicians.

Section snippets

General scope and objectives

These guidelines focus on autoimmune encephalitis that presents with subacute onset of memory deficits or altered mental status, accompanied or not by other symptoms and manifestations, with the goal of helping to establish a prompt diagnosis. These guidelines do not address the clinical approach to other CNS autoimmune disorders (stiff person syndrome,24 progressive encephalomyelitis with rigidity and myoclonus,25 or autoimmune cerebellopathies26) that usually present with a clinical profile

Methods

An initial draft of these guidelines was developed by two authors (FG and JD) and subsequently underwent three rounds of reviews and updates by a panel of investigators who have expertise in autoimmune encephalitis. In the first stage, we reviewed previously published guidelines and diagnostic criteria for encephalitis (of any cause or idiopathic). This review along with clinical experience with forms of autoimmune encephalitis described in the past 10 years (eg, some of them not necessarily

Initial clinical assessment: possible autoimmune encephalitis

We regard a patient with new-onset encephalitis as having possible autoimmune encephalitis if the criteria shown in panel 1 are met. These criteria differ from those previously proposed for encephalitis (any cause or idiopathic) in which changes in the level of consciousness, fever, CSF pleocytosis, and EEG alterations are more often needed.1, 4, 5, 6 These criteria needed to be adapted for autoimmune encephalitis because patients with autoimmune encephalitis could present with memory or

Approach to patients with clinically recognisable syndromes

A substantial number of patients with autoimmune encephalitis do not present with a well defined syndrome. In some of these patients, demographic information and some comorbidities (eg, diarrhoea, ovarian teratoma, faciobrachial dystonic seizures) might initially suggest the underlying disorder (anti-dipeptidyl-peptidase-like protein-6 [DPPX], anti-NMDA receptor, anti-leucine-rich, glioma-inactivated 1 [LGI1] encephalitis), but these features are not pathognomonic and might be absent in some

Antibody testing: clinical considerations and caveats

The detection of specific autoantibodies (table, figure 1) establishes a definitive diagnosis of autoimmune encephalitis, identifies immunological subtypes of limbic encephalitis, and assists in the differential diagnosis of atypical clinical cases. Therefore, measurement of antibodies is a crucial step in the definite diagnosis of many types of autoimmune encephalitis and clinicians must be aware of potential pitfalls in the interpretation of results.

Several concepts that apply to classic

Approach to patients without recognisable syndromes or autoantibodies

After excluding all well characterised syndromes of autoimmune encephalitis (with or without autoantibodies) and other syndromes accompanied by well defined autoantibodies, a group of patients who have possible autoimmune encephalitis will remain (panel 1). Patients in this group can be regarded as having probable autoimmune encephalitis if they satisfy criteria for Hashimoto's encephalopathy (panel 6)101 or the criteria proposed in panel 7.

The definition of Hashimoto's encephalopathy has been

Implications and directions for future research

We have shown that it is possible to proceed through a logical differential diagnosis of autoimmune encephalitis using criteria based on conventional clinical neurological assessment and standard diagnostic tests (MRI, EEG, and CSF studies). Through this approach, levels of evidence of probable and definite autoimmune encephalitis can be achieved early and therapies implemented quickly, with the possibility of fine-tuning the diagnosis and treatment when antibody results become available.

Search strategy and selection criteria

Relevant papers were identified through PubMed searches of articles published in English up to Nov 23, 2015, using the search terms (alone or in combination): “autoimmune encephalitis”, “limbic encephalitis”, “anti-NMDA receptor encephalitis”, “ acute disseminated encephalomyelitis”, “brainstem encephalitis”, “basal ganglia encephalitis”, “Hashimoto encephalopathy”, “Rasmussen encephalitis”, “primary CNS angiitis”, “primary CNS vaculitis”, “Susac syndrome”, “Morvan syndrome”, and “neuronal

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