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
Position PaperA clinical approach to diagnosis of autoimmune encephalitis
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
References (109)
- et al.
Development of case definitions for acute encephalopathy, encephalitis, and multiple sclerosis reports to the vaccine: Adverse Event Reporting System
J Clin Epidemiol
(2002) - et al.
Encephalitis, myelitis, and acute disseminated encephalomyelitis (ADEM): case definitions and guidelines for collection, analysis, and presentation of immunization safety data
Vaccine
(2007) - et al.
Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis
Lancet Neurol
(2011) - et al.
Antibodies to the GABA(B) receptor in limbic encephalitis with seizures: case series and characterisation of the antigen
Lancet Neurol
(2010) - et al.
Encephalitis with refractory seizures, status epilepticus, and antibodies to the GABAA receptor: a case series, characterisation of the antigen, and analysis of the effects of antibodies
Lancet Neurol
(2014) - et al.
Investigation of LGI1 as the antigen in limbic encephalitis previously attributed to potassium channels: a case series
Lancet Neurol
(2010) - et al.
Clinical presentation of immune-mediated cerebellar ataxia
Rev Neurol (Paris)
(2011) - et al.
Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study
Lancet Neurol
(2013) - et al.
Management of suspected viral encephalitis in adults—association of British Neurologists and British Infection Association National Guidelines
J Infect
(2012) - et al.
Imaging of autoimmune encephalitis – Relevance for clinical practice and hippocampal function
Neuroscience
(2015)
CSF findings in patients with voltage gated potassium channel antibody associated limbic encephalitis
J Neurol Sci
The spectrum of post-vaccination inflammatory CNS demyelinating syndromes
Autoimmun Rev
A brief review of Susac syndrome
J Neurol Sci
Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies
Lancet Neurol
Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: a retrospective study
Lancet Neurol
CSF findings in patients with anti-N-methyl-D-aspartate receptor-encephalitis
Seizure
Insights into antibody-associated encephalitis—Bickerstaff's 1950's papers revisited
J Neurol Sci
Cerebrospinal fluid findings in aquaporin-4 antibody positive neuromyelitis optica: results from 211 lumbar punctures
J Neurol Sci
Case definitions, diagnostic algorithms, and priorities in encephalitis: consensus statement of the international encephalitis consortium
Clin Infect Dis
The incidence of acute encephalitis syndrome in Western industrialised and tropical countries
Virol J
Burden of encephalitis-associated hospitalizations in the United States, 1998–2010
Neurology
Consensus guidelines for the investigation and management of encephalitis in adults and children in Australia and New Zealand
Intern Med J
Autoimmune encephalopathies
Ann N Y Acad Sci
Limbic encephalitis and small cell lung cancer. Clinical and immunological features
Brain
Clinical analysis of anti-Ma2-associated encephalitis
Brain
Antibodies to glutamic acid decarboxylase define a form of limbic encephalitis
Ann Neurol
AMPA receptor antibodies in limbic encephalitis alter synaptic receptor location
Ann Neurol
Antibodies to metabotropic glutamate receptor 5 in the Ophelia syndrome
Neurology
Antibodies to surface dopamine-2 receptor in autoimmune movement and psychiatric disorders
Brain
Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan's syndrome and acquired neuromyotonia
Brain
Encephalitis and antibodies to dipeptidyl-peptidase-like protein-6, a subunit of Kv4.2 potassium channels
Ann Neurol
Antibodies to native myelin oligodendrocyte glycoprotein in children with inflammatory demyelinating central nervous system disease
Ann Neurol
CNS aquaporin-4 autoimmunity in children
Neurology
Bickerstaff brainstem encephalitis and Fisher syndrome: anti-GQ1b antibody syndrome
J Neurol Neurosurg Psychiatry
Paraneoplastic neurological syndromes and glutamic acid decarboxylase antibodies
JAMA Neurol
Immunology of stiff person syndrome and other GAD-associated neurological disorders
Expert Rev Clin Immunol
Glycine receptor antibodies in PERM and related syndromes: characteristics, clinical features and outcomes
Brain
Central nervous system neuronal surface antibody associated syndromes: review and guidelines for recognition
J Neurol Neurosurg Psychiatry
Earlier treatment of NMDAR antibody encephalitis in children results in a better outcome
Neurol Neuroimmunol Neuroinflamm
Treatment-responsive limbic encephalitis identified by neuropil antibodies: MRI and PET correlates
Brain
Potassium channel antibody-associated encephalopathy: a potentially immunotherapy-responsive form of limbic encephalitis
Brain
International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-mediated central nervous system demyelinating disorders: revisions to the 2007 definitions
Mult Scler
Hashimoto's encephalopathy
Ann N Y Acad Sci
Morvan syndrome: clinical and serological observations in 29 cases
Ann Neurol
Pathogenesis, diagnosis and treatment of Rasmussen encephalitis: a European consensus statement
Brain
Autoimmune encephalitis in children
J Child Neurol
Infectious and autoantibody-associated encephalitis: clinical features and long-term outcome
Pediatrics
Extreme delta brush: a unique EEG pattern in adults with anti-NMDA receptor encephalitis
Neurology
Patients with suspected herpes simplex encephalitis: rethinking an initial negative polymerase chain reaction result
Clin Infect Dis
DPPX potassium channel antibody: frequency, clinical accompaniments, and outcomes in 20 patients
Neurology
Cited by (2580)
Genetic causes of infection induced encephalitis
2024, European Journal of Paediatric NeurologyAutoimmune encephalitis in Israeli children – A retrospective nationwide study
2024, European Journal of Paediatric NeurologyUtilization of APE2 and RITE2 scores in autoimmune encephalitis patients with seizures
2024, Epilepsy and BehaviorExclusion of alternative diagnoses: A component of the 2023 MOGAD criteria that belongs at the forefront, not in the background
2024, Multiple Sclerosis and Related DisordersAutoimmune central nervous system disorders: Antibody testing and its clinical utility
2024, Clinical Biochemistry