Clinical approach to the diagnosis of autoimmune encephalitis in the pediatric patient

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Abstract

Objective

Autoimmune encephalitis (AE) is an important and treatable cause of acute encephalitis. Diagnosis of AE in a developing child is challenging because of overlap in clinical presentations with other diseases and complexity of normal behavior changes. Existing diagnostic criteria for adult AE require modification to be applied to children, who differ from adults in their clinical presentations, paraclinical findings, autoantibody profiles, treatment response, and long-term outcomes.

Methods

A subcommittee of the Autoimmune Encephalitis International Working Group collaborated through conference calls and email correspondence to consider the pediatric-specific approach to AE. The subcommittee reviewed the literature of relevant AE studies and sought additional input from other expert clinicians and researchers.

Results

Existing consensus criteria for adult AE were refined for use in children. Provisional pediatric AE classification criteria and an algorithm to facilitate early diagnosis are proposed. There is also discussion about how to distinguish pediatric AE from conditions within the differential diagnosis.

Conclusions

Diagnosing AE is based on the combination of a clinical history consistent with pediatric AE and supportive diagnostic testing, which includes but is not dependent on antibody testing. The proposed criteria and algorithm require validation in prospective pediatric cohorts.

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Most cited references 38

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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

Sarosh R. Irani, Sian Alexander, Patrick Waters … (2010)

Antibodies that immunoprecipitate 125I-α-dendrotoxin-labelled voltage-gated potassium channels extracted from mammalian brain tissue have been identified in patients with neuromyotonia, Morvan’s syndrome, limbic encephalitis and a few cases of adult-onset epilepsy. These conditions often improve following immunomodulatory therapies. However, the proportions of the different syndromes, the numbers with associated tumours and the relationships with potassium channel subunit antibody specificities have been unclear. We documented the clinical phenotype and tumour associations in 96 potassium channel antibody positive patients (titres >400 pM). Five had thymomas and one had an endometrial adenocarcinoma. To define the antibody specificities, we looked for binding of serum antibodies and their effects on potassium channel currents using human embryonic kidney cells expressing the potassium channel subunits. Surprisingly, only three of the patients had antibodies directed against the potassium channel subunits. By contrast, we found antibodies to three proteins that are complexed with 125I-α-dendrotoxin-labelled potassium channels in brain extracts: (i) contactin-associated protein-2 that is localized at the juxtaparanodes in myelinated axons; (ii) leucine-rich, glioma inactivated 1 protein that is most strongly expressed in the hippocampus; and (iii) Tag-1/contactin-2 that associates with contactin-associated protein-2. Antibodies to Kv1 subunits were found in three sera, to contactin-associated protein-2 in 19 sera, to leucine-rich, glioma inactivated 1 protein in 55 sera and to contactin-2 in five sera, four of which were also positive for the other antibodies. The remaining 18 sera were negative for potassium channel subunits and associated proteins by the methods employed. Of the 19 patients with contactin-associated protein-antibody-2, 10 had neuromyotonia or Morvan’s syndrome, compared with only 3 of the 55 leucine-rich, glioma inactivated 1 protein-antibody positive patients (P < 0.0001), who predominantly had limbic encephalitis. The responses to immunomodulatory therapies, defined by changes in modified Rankin scores, were good except in the patients with tumours, who all had contactin-associated-2 protein antibodies. This study confirms that the majority of patients with high potassium channel antibodies have limbic encephalitis without tumours. The identification of leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 as the major targets of potassium channel antibodies, and their associations with different clinical features, begins to explain the diversity of these syndromes; furthermore, detection of contactin-associated protein-2 antibodies should help identify the risk of an underlying tumour and a poor prognosis in future patients.

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Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis in children and adolescents.

Nicole R Florance, Rebecca L. Davis, Christopher Lam … (2009)

To report the clinical features of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis in patients 18 years old, 31% in girls < or =18 years old (p = 0.05), and 9% in girls < or =14 years old (p = 0.008). None of the male patients had tumors. Of 32 patients < or =18 years old, 87.5% presented with behavioral or personality change, sometimes associated with seizures and frequent sleep dysfunction; 9.5% with dyskinesias or dystonia; and 3% with speech reduction. On admission, 53% had severe speech deficits. Eventually, 77% developed seizures, 84% stereotyped movements, 86% autonomic instability, and 23% hypoventilation. Responses to immunotherapy were slow and variable. Overall, 74% had full or substantial recovery after immunotherapy or tumor removal. Neurological relapses occurred in 25%. At the last follow-up, full recovery occurred more frequently in patients who had a teratoma that was removed (5/8) than in those without a teratoma (4/23; p = 0.03). Anti-NMDAR encephalitis is increasingly recognized in children, comprising 40% of all cases. Younger patients are less likely to have tumors. Behavioral and speech problems, seizures, and abnormal movements are common early symptoms. The phenotype resembles that of the adults, although dysautonomia and hypoventilation are less frequent or severe in children. Ann Neurol 2009;66:11-18.

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The frequency of autoimmune N-methyl-D-aspartate receptor encephalitis surpasses that of individual viral etiologies in young individuals enrolled in the California Encephalitis Project.

Mary S Gable, Heather Sheriff, Josep Dalmau … (2012)

In 2007, the California Encephalitis Project (CEP), which was established to study the epidemiology of encephalitis, began identifying cases of anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis. Increasing numbers of anti-NMDAR encephalitis cases have been identified at the CEP, and this form rivals commonly known viral etiologies as a causal agent. We report here the relative frequency and differences among encephalitides caused by anti-NMDAR and viral etiologies within the CEP experience. Demographic, frequency, and clinical data from patients with anti-NMDAR encephalitis are compared with those with viral encephalitic agents: enterovirus, herpes simplex virus type 1 (HSV-1), varicella-zoster virus (VZV), and West Nile virus (WNV). All examined cases presented to the CEP between September 2007 and February 2011 and are limited to individuals aged ≤30 years because of the predominance of anti-NMDAR encephalitis in this group. The diagnostic costs incurred in a single case are also included. Anti-NMDAR encephalitis was identified >4 times as frequently as HSV-1, WNV, or VZV and was the leading entity identified in our cohort. We found that 65% of anti-NMDAR encephalitis occurred in patients aged ≤18 years. This disorder demonstrated a predilection, which was not observed with viral etiologies, for females (P < .01). Seizures, language dysfunction, psychosis, and electroencephalographic abnormalities were significantly more frequent in patients with anti-NMDAR encephalitis (P < .05), and autonomic instability occurred exclusively in this group. Anti-NMDAR encephalitis rivals viral etiologies as a cause of encephalitis within the CEP cohort. This entity deserves a prominent place on the encephalitic differential diagnosis to avoid unnecessary diagnostic and treatment costs, and to permit a more timely treatment.

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Author and article information

Journal

Journal ID (nlm-ta): Neurol Neuroimmunol Neuroinflamm

Journal ID (iso-abbrev): Neurol Neuroimmunol Neuroinflamm

Journal ID (hwp): nnn

Journal ID (publisher-id): NEURIMMINFL

Title: Neurology® Neuroimmunology & Neuroinflammation

Publisher: Lippincott Williams & Wilkins (Hagerstown, MD )

ISSN (Electronic): 2332-7812

Publication date Collection: March 2020

Publication date (Electronic): 17 January 2020

Publication date PMC-release: 17 January 2020

Volume: 7

Issue: 2

Electronic Location Identifier: e663

Affiliations

From the Department of Pediatrics (T.C.), McMaster Children's Hospital, McMaster University, Hamilton, Ontario, Canada; Department of Pediatrics (H.V.M.), Duke University, Durham, NC; Neuroimmunology Program (F.G., J.D.), Institut d'Investigacions Biomèdiques August Pi I Sunyer, Barcelona, Spain; Department of Pediatrics (E.M.), Baylor College of Medicine, Houston, TX; Department of Neurology (W.G., K.V.H.), Lucile Packard Children's Hospital, Stanford University, Palo Alto, CA; Division of Rheumatology (M.S.K.-G.), Ann & Robert H, Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, IL; Department of Pediatrics (S.M.B.), Alberta Children's Hospital, University of Calgary, Canada; Division of Pediatric Allergy, Immunology and Rheumatology (J.F.), Lucile Packard Children's Hospital, Stanford University, Palo Alto, CA; Department of Neurology (M.P.G.), Boston Children's Hospital, Harvard University, MA; Department of Neurology (J.D.), University of Pennsylvania, Philadelphia; Catalan Institution for Research and Advanced Studies (ICREA) (J.D.); Neuroimmunology Group (R.C.D.), Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, New South Wales, Australia.

Author notes

Correspondence Dr. Dale Russell.dale@ 123456health.nsw.gov.au

Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article.

The Article Processing Charge was funded by Neurology: Neuroimmunology & Neuroinflammation.

Article

Publisher ID: NEURIMMINFL2019022913

DOI: 10.1212/NXI.0000000000000663

PMC ID: 7051207

PubMed ID: 31953309

SO-VID: 2bc3cee0-7438-4e97-9d9f-6ba4277fe1da

License:

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

Date received : 31 July 2019

Date accepted : 25 November 2019

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Clinical approach to the diagnosis of autoimmune encephalitis in the pediatric patient

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Abstract

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Methods

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Cures Within Reach: Autoimmune Lymphoproliferative Syndrome (ALPS)

Most cited references 38

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

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis in children and adolescents.

The frequency of autoimmune N-methyl-D-aspartate receptor encephalitis surpasses that of individual viral etiologies in young individuals enrolled in the California Encephalitis Project.

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Cited by 78

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