Accepted Manuscript

Utility of Neurodiagnostic Studies in the Diagnosis of Autoimmune Encephalitis in

Children

Dara V. Albert, DO, Charles P. Pluto, MD, PhD, Amanda Weber, DO, Jorge Vidaurre,
MD, Fatima Barbar-Smiley, MD, MPH, Rabheh Abdul Aziz, MD, Kyla Driest, MD,
Sharon Bout-Tabaku, MD, MSCE, Lynne Ruess, MD, Jerome A. Rusin, MD, Bethanie
Morgan-Followell, MD

PII: S0887-8994(15)30255-1
DOI: 10.1016/j.pediatrneurol.2015.10.016
Reference: PNU 8776

To appear in: Pediatric Neurology

Received Date: 22 October 2015

Accepted Date: 31 October 2015

Please cite this article as: Albert DV, Pluto CP, Weber A, Vidaurre J, Barbar-Smiley F, Aziz RA,
Driest K, Bout-Tabaku S, Ruess L, Rusin JA, Morgan-Followell B, Utility of Neurodiagnostic Studies
in the Diagnosis of Autoimmune Encephalitis in Children, Pediatric Neurology (2015), doi: 10.1016/
j.pediatrneurol.2015.10.016.

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 ACCEPTED MANUSCRIPT

Utility of Neurodiagnostic Studies in the Diagnosis of Autoimmune Encephalitis in Children

Dara V. Albert, DO1,2*, Charles P. Pluto, MD, PhD2,3*, Amanda Weber, DO1, Jorge Vidaurre, MD1,2,
Fatima Barbar-Smiley, MD, MPH4; Rabheh Abdul Aziz, MD4, Kyla Driest, MD2,4,, Sharon Bout-
Tabaku, MD, MSCE2,4, Lynne Ruess, MD2,3, Jerome A. Rusin, MD2,3, Bethanie Morgan-Followell,
MD1,2
1
Section of Child Neurology, Department of Pediatrics, Nationwide Children’s Hospital,

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Columbus, Ohio
2
College of Medicine, The Ohio State University, Columbus, Ohio
3
Department of Radiology, Nationwide Children’s Hospital, Columbus, Ohio
4

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Section of Rheumatology, Department of Pediatrics, Nationwide Children’s Hospital, Columbus,
Ohio

*Co-first authors

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Corresponding author:

Bethanie Morgan-Followell, MD

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Section of Child Neurology, Nationwide Children's Hospital
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700 Children’s Drive

Columbus, OH 43205
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Phone 614-722-4625, Fax 614-722-4633

Email: Bethanie.morgan@nationwidechildrens.org
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Co-Author Contact Information:

Dara V. Albert, DO Dara.albert@nationwidechildrens.org
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Charles P. Pluto, MD, PhD cpluto@raaonline.com

Amanda Weber, DO Amanda.weber@nationwidechildrens.org
Jorge Vidaurre, MD Jorge.vidaurre@nationwidechildrens.org
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Fatima Barbar-Smiley, MD, MPH Fatima.barbarSmiley@nationwidechildrens.org

Kyla Driest, MD Kyla.driest@nationwidechildrens.org
Rabheh Abdul Aziz, MD Rabheh.abdulAziz@nationwidechildrens.org
Sharon Bout-Tabaku, MD, MSCE Sharon.bout-tabaku@nationwidechildrens.org
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Lynne Ruess, MD Lynne.ruess@nationwidechildrens.org

Jerome Rusin, MD Jerome.rusin@nationwidechildrens.org
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Disclosures: All authors report no disclosures

Funding: N/A

Article Type: Original Article

Abstract word count: 244 Manuscript word count: 3072

Key words: autoimmune encephalitis, magnetic resonance imaging (MRI), electroencephalogram (EEG),
NMDA antibody, GAD-65 antibody, TPO antibody
 ACCEPTED MANUSCRIPT

Abstract

Objective: To identify disease specific patterns of neurodiagnostic studies (MRI and EEG) for

autoimmune encephalitis in children.

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Background: Autoimmune encephalitis is currently a clinical diagnosis without widely accepted

diagnostic criteria often leading to a delay in diagnosis. The utility of MRI and EEG in this disease is

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unknown.

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Methods: A retrospective chart review of encephalopathic patients seen at a large pediatric hospital over 4

years was performed. Clinical presentation, autoantibody status, MRI and EEG findings were described

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and compared. Those with autoantibodies were considered “definite” cases while those without antibodies
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or those with only TPO antibodies were “suspected”.

Results: Eighteen patients met inclusion criteria and autoantibodies were identified in 9. The patients with
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definite autoimmune encephalitis had MRI abnormalities within limbic structures most notably the

anteromedial temporal lobes (56%). Only patients with suspected cases had non-temporal lobe cortical
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lesions. Sixteen patients had an EEG and 13 (81%) were abnormal. The most common findings were
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abnormal background (63%), generalized slowing (50%), focal slowing (43%) and focal epileptiform

discharges (31%). An additional interesting finding was sleep spindle abnormalities present in 38% of
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patients. There were no specific differences in the EEGs between the definite and suspected cases. Focal

EEG findings only correlated with a focal lesion on MRI in a single definite case.
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Conclusions: Pediatric patients with definite autoimmune encephalitis have a narrow spectrum of MRI

abnormalities. Conversely, EEGs abnormalities are mostly nonspecific. All patients in our cohort had

abnormalities on one or both neurodiagnostic studies.

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Introduction

Autoimmune encephalitis is an increasingly identified cause of encephalitis when no infectious agent is

apparent. As many as 77% of children with autoimmune encephalitis will have seizures during the course

of the illness; thus, the terms “autoimmune encephalitis” and “autoimmune epilepsy” have significant

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overlap though each may exist independently1,2. Clinical signs and symptoms of concern for autoimmune

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encephalitis and autoimmune epilepsy have been published. These rely on the identification of neuronal

surface antibodies (NSAbs) and an intracellular antibody, glutamic acid decarboxylase (GAD), to make a

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diagnosis of “definite” autoimmune encephalitis or epilepsy. Presently, only a handful of antibodies

thought to be pathogenic have been identified. In addition, testing is not commercially available for all

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antibodies associated with autoimmune encephalitis and epilepsy. Given the limited availability of
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biomarkers to make a definitive diagnosis, patients often fall into the category of “suspected”

autoimmune encephalitis or epilepsy. The diagnosis of suspected relies on non-specific clinical symptoms
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and is in many ways a diagnosis of exclusion. Thus, prompt identification of patients with autoimmune

encephalitis and/or epilepsy is often difficult. Prompt diagnosis is imperative as literature has shown that
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early treatment improves outcomes3. As more pathogenic antibodies are identified and testing becomes
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widely available, time to diagnosis and treatment will decrease. While awaiting these developments, we

can seek to maximize the yield of current neurodiagnostic testing, specifically magnetic resonance
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imaging (MRI) and electroencephalography (EEG).

The utility of neurodiagnostic studies, namely brain MRI and EEG, in the setting of autoimmune
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encephalitis is unclear. Several recent papers have described MRI findings of autoimmune encephalitis in
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adults, but relatively little is published about MRI findings of autoimmune encephalitis in children4-7.

MRI can range from completely normal to significantly abnormal. Increased T2 signal abnormality in the

limbic regions has been previously described6. Prior studies have shown that many patients will have

abnormal EEGs and authors have attempted to elucidate common abnormalities1,2,6,8-12. Unfortunately,
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most have found only non-specific EEG abnormalities such as generalized slowing and epileptiform

discharges5,13

We examined brain MRIs and EEGs from 18 children with either definite or suspected autoimmune

encephalitis. The primary objective of this retrospective case series was to identify disease specific

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patterns of neurodiagnostic studies (MRI and EEG) for autoimmune encephalitis in children. We

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hypothesized that common features may emerge which would aid in the diagnosis and also that there

might be differences in findings between those with definite versus suspected autoimmune encephalitis.

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Methods

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This study was submitted to and approved by the Nationwide Children’s Hospital Internal Review Board.
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Retrospective chart review of children with definite or suspected autoimmune encephalitis at

Nationwide Children’s Hospital from January 2009 to December 2013 was performed by five
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physicians (AW, KD, FBS, RAA, SBT). We identified 244 patients with “encephalitis” (ICD-9

323.01 to 323.9) or “encephalopathy” (ICD-9 348.30 to 348.39) as a primary or secondary

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diagnosis in the electronic medical record. We developed inclusion criteria based on the available
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pediatric literature in autoimmune encephalitis/epilepsy (Figure 1)13,14. Demographic information

and clinical data including signs and symptoms at presentation and follow up, laboratory results,
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and treatment regimens were recorded. This information was then reviewed by a

neuroimmunologist (BMF) to ensure that the criteria were appropriate.

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All MRIs were performed on 1.5 or 3 Tesla GE magnets; gadopentetate dimeglumine

(Magnevist) MRI contrast was used. All MRIs were independently reviewed by two pediatric

neuroradiologists (CP and JR). The radiologists then reviewed all of the cases together and any

examinations with questionable findings were reviewed by a third pediatric radiologist (LR) who

was blinded to the finding(s) in question.

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EEGs were performed using the standard 10/20 international system of electrode placement. When

patients had more than one EEG, only the initial EEG was reviewed. If a patient had more than 24 hours

of video EEG monitoring, only the first 24 hours were reviewed. All EEGs were reviewed by two

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neurophysiologists (DVA and JV). The neurophysiologists were aware that the patients had the diagnosis

of either definite or suspected autoimmune encephalitis, but were blinded to the clinical information at the

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time of review.

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Results

1. Clinical and Laboratory

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There were 244 pediatric patients identified by review of the electronic medical record; 18 met

inclusion criteria (Figure 1). There were 12 (67%) females and 6 (33%) males. The mean age was
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10.1 years at presentation. Ethnic background of the patients were as follows: 6 (33%) patients
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were Caucasian, 7 (39%) African-American and the remaining 5 (28%) were other or of mixed

heritage. The most common presenting symptom was seizure in 56%. Fever was documented on
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clinical presentation in 33%. Seventeen of 18 patients had cerebrospinal fluid examination. Ten

(56%) of those had 5 or more WBCs per cubic millimeter. Six (33%) of 17 had CSF protein
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greater than 45 mg/dL. Both WBCs and protein were adjusted for number of RBCs using the

standard correction calculation (allowance of 1 WBC for every 700 RBCs and protein increases
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1.1 mg/dl for every 1000 RBCs) (15). Eight patients had testing for oligoclonal bands. Unpaired
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oligoclonal bands were present in the CSF of 4. Six patients had other autoimmune disorders: 1

type I diabetes mellitus, 3 transient thyroiditis associated with anti-TPO antibodies, 1 alopecia

areata, and 1 type I diabetes mellitus and Grave’s disease. Mean duration of follow-up was 25

months (range 1-79 months).

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Antibody testing was performed at the discretion of the treating physician and was, therefore,

highly variable. Neuronal surface antibodies (NSAbs) were identified in 5 patients and all these

were anti-NMDA receptor antibodies. Glutamic acid decarboxylase antibodies (GAD 65)

antibodies were identified in 4 patients. In all, we identified 9 definite cases of autoimmune

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encephalitis via antibody testing in either serum or CSF. All other cases were classified as

suspected cases based on the fulfillment of clinical inclusion criteria. Given the poorly

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understood significance of TPO antibodies, patients with TPO antibodies alone were classified as

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suspected.

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Anti-thyroperoxidase (TPO) antibodies were identified in 4 patients. Anti-GAD 65 antibodies

were concurrently present in 2 of these patients. Three patients were diagnosed with thyroiditis
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associated with anti-TPO antibodies by the consultant endocrinologist. Two had a transient

elevation in serum TSH without elevation in serum T3 or T4 while the third had both normal
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TSH and normal T3/T4. Two (one with elevated TSH, one with normal TSH) had findings on
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ultrasonography of the neck suggestive of thyroiditis. One had no imaging of the thyroid gland.
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One patient with anti-TPO antibodies was diagnosed with Grave’s disease. He had elevated

serum T3 and T4 with low TSH. Radioactive iodine uptake (RAIU) of the thyroid gland was
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elevated, consistent with the diagnosis of Grave’s disease. None of the patients with anti-TPO

antibodies had clinical symptoms suggestive of thyroid dysfunction documented in the medical
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record.
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Medical treatment was variable and at the discretion of the treating physician. Corticosteroids

were most commonly used with various combinations of additional therapies including

intravenous immunoglobulin (IVIG), mycophenolate mofetil, cyclophosphamide, and rituximab.

Eight (44%) patients had epilepsy at follow-up. Half of the patients had residual epilepsy and the

majority of patients had some neurologic sequelae.

 ACCEPTED MANUSCRIPT

2. MRI

Seventeen of the patients had at least 1 MRI of the brain available for review. Thirteen of 17 (76%) had

an abnormal MRI of the brain. Seven of the 9 patients (78%) with definite autoimmune encephalitis had

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abnormalities on initial brain MRIs. Increased T2 signal on FLAIR images was the predominant MRI

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abnormality, seen in all patients with an abnormal MRI. Abnormal contrast enhancement was seen in 7 of

13 (54%) patients with abnormal MRI, with scattered sulcal, rather than parenchymal enhancement being

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most common.

The limbic structures were involved in 7 of 9 definite cases (Table 1, Figure 2). Involvement was

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predominately bilateral and asymmetric. Definite cases had T2 FLAIR signal abnormality in the
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hippocampus, amygdala, uncinate, gyrus rectus, cingulate gyrus, and/or anteromedial temporal lobe

cortex. Insular cortex involvement was seen in 4 definite and 3 suspected cases (Figure 3). There were 5
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suspected cases with abnormal MRI. These had extra-limbic cortical involvement (non-limbic temporal
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lobe structures, parietal and/or occipital lobes) that tended to be bilateral and asymmetric. Only one

suspected case had limbic involvement. Both definite and suspected cases had deep gray matter signal
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abnormality.
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3. EEG

Sixteen patients had EEG studies available for review. Of the patients who had EEGs, twelve patients
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(75%) had clinical seizures at presentation; however only 3 patients (19%) had seizures which were
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captured on EEG. Of those three, one patient had electroclinical seizures, electrographic seizures and

status epilepticus. In all 3 patients with seizures on EEG, the frontotemporal regions were involved and

anti-GAD 65 antibodies were identified in 2 (67%). One of these patients had signal abnormality in the

left frontal subcortical white matter on MRI which correlated with seizures arising from the left frontal
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region. Of the patients whose initial clinical presentation included seizures, 6 (50%) were found to have

either anti-NMDA receptor antibodies or anti-GAD 65 antibodies.

Of the 16 patients who had EEG studies, 13 (81%) had inter-ictal and background abnormalities on EEG.

The most common findings were non-specific abnormalities of the background (63%), generalized

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slowing (50%), and focal slowing (43%). When epileptiform discharges were present (38%), they were

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most commonly focal (80%). In 3 patients with focal abnormalities on EEG, there was some correlation

with MRI findings. One patient had signal change abnormality in the left frontal subcortical white matter

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and had electrographic seizures and interictal discharges arising from the left frontal region (Figure 4).

Another patient had multifocal MRI changes including right hippocampal involvement and had focal

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discharges over the right anterior temporal region. The final patient had bilateral, left greater than right
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signal change in parietal-occipital area and had focal slowing over the left posterior quadrant on EEG.

Generalized discharges were only seen in 1 patient. EEG abnormalities were present in both the definite
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autoimmune encephalitis cases (82%) and the suspected (67%) cases. A relatively small number had

seizures captured on EEG (3/16). However, most of the patients received an anticonvulsant at the time of
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or prior to their study (56%).

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A new finding that has not been described previously was sleep spindle abnormalities. This was present in

38% of all patients. Both asynchrony and prolongation of sleep spindles were noted (Figure 5). We
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specifically examined the tracings for the extreme delta brush pattern that has been described in adults

with anti-NMDA receptor encephalitis and did not find this pattern in any of our study patients.
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Discussion

In the past decade, autoimmune encephalitis has been recognized as a cause of encephalopathy in children

and adolescents when no infectious agent can be identified. Its diagnosis is largely one of exclusion and

relies heavily on the experience of the treating physician to recognize suggestive clinical features.

Neurodiagnostic modalities including brain MRI and EEG are currently only used as ancillary evidence
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that may support the diagnosis of autoimmune encephalitis. In this study, we retrospectively examined the

results of these tests in order to better understand their potential use as objective evidence to support the

diagnosis of autoimmune encephalitis in children.

Only 28% of children in our study, and only 2 of the definite cases, had normal brain MRIs on clinical

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presentation. The frequency of abnormal brain MRI is significantly higher in our study than in previously

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published series. In a series of 48 children, both with definite and suspected autoimmune encephalitis,

73% had normal brain MRIs at presentation5. Another 2013 series of 13 children with autoimmune

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epilepsy showed 67% with normal brain MRIs15 . A 2009 series of children with anti-NMDA receptor

encephalitis had 69% with normal brain MRIs. More than half of those with abnormalities on initial

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imaging had only transient abnormalities1.
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In our series, most patients with definite autoimmune encephalitis had abnormalities on brain MRI.

Abnormal T2 signal in the limbic structures was more often seen in patients with definite autoimmune
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encephalitis and extra-limbic cortical involvement was more often seen in suspected cases. The
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differences in brain MRI signal abnormalities between definite and suspected cases of autoimmune

encephalitis suggest that cortical neurons in limbic structures may be preferentially targeted by anti-
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NMDA receptor antibodies and anti-GAD 65 antibodies. The anti-NMDA receptor antibody is involved

in plasticity, learning and memory that takes place largely in the hippocampi and limbic structures16,17.
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Four of the 5 patients with anti-NMDA receptor showed limbic involvement, and 2 showed thalamic

involvement. There was one child with suspected autoimmune encephalitis who had limbic involvement
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on brain MRI. His clinical presentation was strongly suggestive of anti-NMDA receptor encephalitis.
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Anti-NMDA receptor antibodies were absent in the CSF, but not tested in the serum. Limited testing for

other neuronal surface antibodies was performed and, therefore, the diagnosis could not be confirmed.

Eighty-one percent of patients in our series had any abnormality on EEG. This number is similar to

previously published series5,15. EEG findings were mostly non-specific and consistent with an
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encephalopathy, which is congruent with previous reports2,3,5,6. Focal EEG findings did not clearly

correlate with brain MRI abnormalities in the majority of children. Of note, however, 6 of the 9 patients

with definite autoimmune encephalitis had focal abnormalities on EEG. Four of these children had anti-

NMDA receptor antibodies. In a recently published series of 8 children with anti-NMDA receptor

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encephalitis, half had focal onset seizures18. This may implicate anti-NMDA receptor antibodies in the

pathogenesis of a small subset of cases of localization-related epilepsy. Suleiman et al found autoimmune

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antibodies in about 10% of pediatric patients with new onset epilepsy of “unknown cause”, many of

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whom had focal-onset seizures. This pilot data suggests that broader screening of children with new onset

of focal seizures for NSAbs and anti-GAD 65 is necessary to determine the prevalence of autoimmune

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epilepsy. Expanding our understanding of autoimmunity as an etiology of childhood epilepsy may lead to

new therapeutic targets, potentially making autoimmune epilepsy the first medically “curable” epilepsy
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syndrome.
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Our study is the first to describe sleep spindle abnormalities in the setting of autoimmune encephalitis

(38%). Four patients had asynchronous sleep spindles. Three of the 4 had definite autoimmune
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encephalitis confirmed by antibody testing. Two other children had prolonged sleep spindles (≥10
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seconds) and anti-TPO antibodies were present in the sera of both. One patient had no testing for NSAbs

or anti-GAD 65 antibodies and the other limited testing (anti-NMDA receptor and anti-GAD 65
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antibodies only). Therefore, no conclusions can be made regarding the significance of anti-TPO

antibodies in these cases. The four children with asynchronous sleep spindles had abnormal brain MRIs
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while the brain MRIs of those with prolonged spindles were normal. Abnormal T2 hyperintensity was
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present in the thalami of two children with asynchronous spindles. Given that sleep spindles are generated

in the thalamus, this is not unexpected. Previous literature examining EEG recordings during sleep in the

setting of anti-NMDA receptor encephalitis in children reported paucity of slow wave rhythms in NREM

sleep19. We reviewed the literature and found no prior reports of sleep spindle abnormalities. Special
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attention to sleep architecture in future studies may provide helpful clue to aid in the early diagnosis of

autoimmune encephalitis.

We did not observe delta brushes in any of the EEG recordings though extra care was taken in attempt to

identify this feature. Delta brushes have been described in association with anti-NMDA receptor

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encephalitis in adults, though in only about a third of patients in one series2. Children with anti-NMDA

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receptor encephalitis as confirmed by laboratory testing comprised only a third of our series. The size of

our sample was likely insufficient for detection of a finding present in a minority of patients. The delta

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brush pattern was initially noted in adults with anti-NMDA receptor encephalitis rather than children, so

perhaps this finding is age-dependent. Based on our review of the literature, the youngest patient with

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anti-NMDA receptor encephalitis reported to have the delta brush pattern was 13 years old18.
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Our cohort of children was relatively small, thus, this may limit the external validity of our findings.

However, our results are comparable to the aforementioned series in most aspects (Table 3). We
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acknowledge that some cases of “suspected” autoimmune encephalitis may have been misclassified as not
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all children meeting clinical criteria had the full complement of commercially available laboratory tests

for NSAbs associated with autoimmune encephalitis and/or anti-GAD 65 antibodies. In addition, we
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recognize the possibility of the existence of other yet to be identified pathogenic NSAbs and/or

intracellular antibodies in the “suspected” patients. This would prompt reclassification of these cases as
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“definite”. As we did not find any significant differences between the “definite” and “suspected” groups,

though, the impact of the incomplete data and unidentified autoantibodies is unclear.
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The neuroradiologists and neurophysiologists who provided interpretation of brain MRIs and of EEGs,

respectively, were not blinded to the patients’ diagnoses of autoimmune encephalitis. This may have

resulted in information/diagnostic suspicion bias. Also with regard to observed brain MRI findings, since

most children in our cohort had seizures early in their clinical course, some MRI findings may have been

post-ictal phenomena rather than the inflammatory changes that were presumably related to autoimmune
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encephalitis. . The results of subsequent neurodiagnostic tests are not included in this study as not all

children had repeat testing, and when testing was performed at the discretion of the treating physician, it

was not performed at any specified time interval from initial clinical presentation. Future research may

focus on whether or not abnormalities on either brain MRI or on EEG resolve, evolve, or persist during

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the convalescent period in children with autoimmune encephalitis.

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Conclusions

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Our findings suggest that the majority of children with autoimmune encephalitis present with

abnormalities on either brain MRI or EEG. Pediatric patients with definite autoimmune encephalitis have

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a narrow spectrum of brain MRI abnormalities seen predominantly in the limbic structures. Conversely,
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EEGs abnormalities are mostly nonspecific regardless of antibody status. We observed abnormalities in

sleep architecture on EEG, specifically, asynchrony or prolongation of sleep spindles in our cohort. The
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correlation of MRI abnormalities in the limbic structures with definite autoimmune encephalitis as

confirmed by the presence of anti-NMDA receptor or anti-GAD 65 antibodies and the observation of
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aberrant sleep spindles on EEG have not been previously reported in the pediatric literature. Future large
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prospective studies of children fulfilling the currently accepted diagnostic criteria for autoimmune

encephalitis are necessary to determine the validity of our observations as well as to provide data on if
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these findings are sensitive and/or specific for pediatric autoimmune encephalitis.
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Tables and Figures

Figure 1. Inclusion criteria for suspected or confirmed autoimmune encephalitis

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Figure 2. 8-year-old Hispanic male who presented with seizures and altered mental status. Anti-NMDA
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receptor antibody was present in the serum and CSF. Coronal T2 FLAIR images obtained 1 day after

presentation show bilateral and symmetric increased signal in the cingulate cortex (A), thalami (B), and
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unilateral right frontal cortex (C).

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A

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C EP
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Figure 3. 7-year-old white male who presented with seizures and abnormal involuntary

movements.. Testing for NSAbs and anti-GAD 65 antibodies was negative. T2 FLAIR (A-C)
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images obtained 3 days after presentation show bilaterally and symmetrically increased signal in

the hippocampi, insula, and anteromedial temporal lobes.

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A AN
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B
C
AC

C
 ACCEPTED MANUSCRIPT

Figure 4. 4.5-year-old girl with anti-GAD 65 antibodies who presented with seizures, behavior changes,

and sleep disturbance. Brain MRI (A) shows left frontal subcortical white matter signal abnormality (blue

circle) on axial T2 proton density sequences. EEG (C) shows polyspikes and electrographic seizures (blue

rectangle) over the left frontal region. EEG is illustrated in the longitudinal bipolar montage in a 10

PT
second epoch.

RI
U SC
AN
M
D
TE

A
C EP
AC

B
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Figure 5. EEG shows asynchronous sleep spindles in a 4-year-old female with anti-GAD 65 antibodies

present in serum. The EEG tracing is shown in the longitudinal bipolar montage in a 10 second epoch.

PT
RI
U SC
AN
M

Table 1. Distribution of increased T2 FLAIR signal in patients with abnormal brain MRI.
D

Definite Suspected
TE

Limbic cortex Hippocampus 6 1

Amygdala + 7
EP

uncinate

Gyrus rectus 2
C

Cingulate 3
AC

gyrus

Anteromedial 7 1

Temporal

Insula 4 3
 ACCEPTED MANUSCRIPT

Other cortex Other 4

Temporal

lobe

Frontal lobe 1

PT
Parietal lobe 4

Occipital lobe 5

RI
Cerebellum 2

SC
Deep gray Thalami 4 1

Caudate 1 1

U
Putamen 3
AN
Table 2. Patient demographics, antibody status, clinical characteristics, and neurodiagnostic findings.
M

Age Gender Definite Antibody Clinical Brain MRI EEG

D

or Symptoms
TE

Suspected

4 F Definite GAD65 Seizures, B/L a-m temporal and Electrographic

EP

psychiatric, L frontal subcortical seizures, focal

sleep white matter discharges,

C

disturbance abnormal
AC

background,

asynchronous

spindles

7 M Suspected None Seizures, fever, B/L symmetric Normal

movement hippocampi, cingulate,

 ACCEPTED MANUSCRIPT

disorder, sleep insula, thalami (R>L)

disturbance

6 M Definite NMDA Seizures, fever, B/L thalami, Generalized and

psychiatric midbrain/peduncles focal slowing,

PT
changes and substantia nigra asynchronous

spindles

RI
10 F Suspected TPO Fever N/A Generalized

SC
slowing,

prolonged

U
AN spindles

16 F Suspected TPO Seizures, Normal Generalized

cognitive and slowing,

M

psychiatric prolonged

symptoms, sleep spindles

D

disturbance,
TE

fever and

associated
EP

infection

7 M Suspected None Seizures, Normal Generalized

C

cognitive and discharges

AC

psychiatric

symptoms, sleep

disturbance

5 F Suspected None Seizures, B/L symmetric a-m Generalized and

cognitive and temporal, occipital, focal slowing,

 ACCEPTED MANUSCRIPT

psychiatric parietal, cingulate, focal discharges,

symptoms, insula thalami electroclinical

dysautonomia, caudates, midbrain, seizures,

associated dorsal pons, R electrographic

PT
infection cerebellar peduncle seizures and

status epilepticus,

RI
asynchronous

SC
spindles

15 F Definite GAD65 Seizures, B/L frontal and a-m Generalized

U
cognitive and
AN temporal, insula, and slowing, focal

psychiatric R hippocampus discharges,

symptoms electroclinical
M

seizures

7 M Definite NMDA Seizures R a-m temporal, Focal slowing,

D

amygdala, uncinate asynchronous

TE

spindles

8 M Definite NMDA Seizures, fever Normal Generalized and

EP

focal slowing

10 F Definite GAD65, Cognitive and B/L symmetric a-m Normal

C

TPO psychiatric temporal, subfrontal,

AC

changes insular, amygdala,

uncini

15 F Suspected None Seizures, Normal Abnormal

movement background, focal

disorder, sleep slowing

 ACCEPTED MANUSCRIPT

disturbance,

fever

10 F Suspected None Seizures, fever B/L but asymmetric Generalized and

(L>R) occipital and focal slowing

PT
parietal

9 F Definite NMDA Seizures, Normal Abnormal

RI
movement PET/CT normal or background, focal

SC
disorder decreased metabolism discharges

in B/L

U
AN occipital/parietal and

thalami

7 F Definite NMDA Psychiatric R a-m temporal, Generalized and

M

changes, insula focal slowing

movement
D

disorder, fever
TE

13 M Definite GAD65, Cognitive and B/L symmetric Normal

TPO psychiatric cingulate, insula,

EP

changes hippocampi,

amygdala, subfrontal,
C

gyrus recti
AC

12 F Suspected None Fever Increase T2 in B/L N/A

thalami and basal

ganglia

17 F Suspected None Fever, seizures, B/L asymmetric N/A

cognitive extensive cortical

 ACCEPTED MANUSCRIPT

changes occipital and

cingulate, L insula,

parietal, frontal

B/L = bilateral, a-m= anterior-medial

PT
Table 3. Comparison of clinical presentation, demographics, and results of neurodiagnostic testing in our

RI
study to previously published series

Hacohen et al, 2013, Suleiman et al, 2013,

SC
Presenting Symptoms Our Series, n=18 n=48 n=13

Fever 33% 35% 46%

Seizure
U
56% 83% 100%
AN
Cognitive 39% 77% 23%

Psychiatric 39% 56% 38%

M

Abnormal movements 17% 38% 23%

D

Sleep disturbance 17% 38% NR

TE

Dysautonomia 6% 13% NR

Demographics
EP

Female 67% 54% 85%

Male 33% 46% 15%

C

Mean age 10.1 8.7 7

AC

Caucasian 33% 50% NR

Black 39% 10% NR

Asian NR 27% NR

Other 28% 13% NR

Mean follow-up 25 24 NR
 ACCEPTED MANUSCRIPT

(months)

Testing

Abnormal brain MRI 71% 38% 33%

Abnormal EEG 81% 96% NR

PT
Abnormal CSF 67% 31% 80%

NR= not reported

RI
U SC
AN
M
D
TE
C EP
AC