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Can J Neurol Sci. Author manuscript; available in PMC 2021 March 30.
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Published in final edited form as:

Can J Neurol Sci. ; : 1–27. doi:10.1017/cjn.2019.305.

Testing for N-methyl-D-aspartate receptor autoantibodies in

clinical practice
John Brooks, MD1, Melanie L Yarbrough, MD2,4, Robert C Bucelli, MD, PhD3,4, Gregory S
Day, MD, MSc3,4
1University of Ottawa; Ottawa, Ontario, Canada
2Department of Pathology and Immunology
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3Department of Neurology
4Washington University School of Medicine, Saint Louis, Missouri, USA

Abstract
BACKGROUND: The diagnosis of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis
relies on the detection of NMDAR IgG autoantibodies in the serum or cerebrospinal fluid of
symptomatic patients. Commercial kits are available that allow NMDAR IgG autoantibodies to be
measured in local laboratories. However, the performance of these tests outside of reference
laboratories is unknown.

OBJECTIVES: To report an unexpectedly low rate of NMDAR autoantibody detection in serum

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from patients with anti-NMDAR encephalitis tested using a commercially available diagnostic kit
in an exemplar clinical laboratory.

METHODS: Paired cerebrospinal fluid and serum samples from seven patients with definite anti-
NMDAR encephalitis were tested for NMDAR IgG autoantibodies using commercially available
cell-based assays run according to manufacturer’s recommendations. Rates of autoantibody
detection in serum tested at our center were compared with those derived through systematic
review and meta-analyses incorporating studies published during or before March 2019.

RESULTS: NMDAR IgG autoantibodies were detected in the cerebrospinal fluid of all patients
tested at our clinical laboratory but not in paired serum samples. Rates of detection were lower
than those previously reported. A similar association was recognized through meta-analyses, with
lower odds of NMDAR IgG autoantibody detection associated with serum testing performed in
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non-reference laboratories.

CONCLUSIONS: Commercial kits may yield lower-than-expected rates of NMDAR IgG

autoantibody detection in serum when run in exemplar clinical (non-reference) laboratories.
Additional studies are needed to decipher the factors that contribute to lower-than-expected rates
of serum positivity. Cerebrospinal fluid testing is recommended in patients with suspected anti-
NMDAR encephalitis.

Corresponding Author: Gregory S Day, Department of Neurology, Washington University School of Medicine, Knight Alzheimer
Disease Research Center, 4488 Forest Park Ave; St. Louis, MO 63108, 314.286.2407 (p), 314.286.1985 (f) gday@wustl.edu.
Author Contribution: Conceptualization, methodology: GSD, JAB. Writing, first draft: JAB. Writing, subsequent drafts and revision:
JAB, GSD, MLY, RCB; Supervision: GSD
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Keywords
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NMDA receptor encephalitis; autoimmune encephalitis; diagnostic testing

Introduction
Since its description in 2007,1 anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is
increasingly recognized as a common, potentially-reversible cause of psychiatric and
neurologic morbidity.2 Early diagnosis and treatment is key to optimizing outcomes,3,4
exemplifying the need for rapid and reliable antibody testing in patients with suspected anti-
NMDAR encephalitis. The detection of IgG autoantibodies against the GluN1 subunit of
central nervous system NMDARs establishes the diagnosis in symptomatic patients.5,6
Although cerebrospinal fluid (CSF) testing remains the gold standard (with sensitivity
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approaching 100%), a prior study evaluating large numbers of samples at a single center
identified NMDAR IgG autoantibodies in the serum of more than 80% of affected patients.7
These findings, if replicated in exemplar clinical environments, could be used to rationalize
serum screening in patient populations and clinical settings where CSF collection is
challenging, impractical or inconvenient, including pediatric populations,8 mental health
settings9 and outpatient clinics.

In response to the growing demand for autoantibody testing, hospital-based laboratories

have begun to test for disease-associated autoantibodies utilizing commercially available
kits. Although in-house testing offers some compelling advantages—namely reduced cost
and turnaround time—the performance characteristics of these tests in newly diagnosed
patients assessed in exemplar clinical environments is unknown. It is imperative that
neurologists appreciate the applications and limitations of autoantibody tests used to support
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or refute a clinical diagnosis, particularly as access to antibody testing continues to expand.

Recognizing this, we reviewed the results of serum NMDAR IgG autoantibody testing in
consecutively-accrued patients with anti-NMDAR encephalitis assessed at our tertiary care
center. Testing was completed on serum samples drawn at the time of antibody detection in
the CSF, using commercially available immunofluorescence assays run in accordance with
the manufacturer’s specifications. Local results were compared with those derived from
systematic review and meta-analysis incorporating published reports providing data
concerning results of serum NMDAR IgG autoantibody testing in patients with definite anti-
NMDAR encephalitis. The potential influence of the laboratory setting and method of
testing on serum NMDAR IgG autoantibody detection was considered via subanalyses of
reported data.
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Methods
Protocol Approvals, Registrations and Patient Consent
Eleven patients were diagnosed with anti-NMDAR encephalitis at Barnes-Jewish Hospital
(BJH; Washington University School of Medicine, Saint Louis, Missouri, USA) from
January 2012 to December 2017. All patients were enrolled in prospective observational
research studies permitting longitudinal clinical evaluation and banking of CSF. Patients met

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clinical criteria for definite anti-NMDAR encephalitis,5 with clinical phenotypes consistent
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with proposed diagnostic criteria (patients presenting with at least one of agitation/
psychosis, dyskinesia, decreased level of consciousness, speech dysfunction, seizure or
dyasautonomia; and anti-NMDAR IgG autoantibodies identified in the CSF). Study
protocols were approved by the Washington University School of Medicine Human
Research Protections Office. Patients or their delegates provided written informed consent
prior to participation.

Autoantibody Testing
Testing for NMDAR IgG autoantibodies was performed by trained laboratory personnel at
Barnes-Jewish Hospital using the commercially available EUROIMMUN Anti-Glutamate
Receptor (type NMDA) immunofluorescence kit (catalog #:FA112d-1005–51)—a cell-based
assay with fixed cells. Cerebrospinal fluid samples were used undiluted, while serum
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samples were diluted 1:10. All testing was performed in accordance with the manufacturer’s
instructions.10 The quoted sensitivity and specificity of the kits for detection of NMDAR
IgG autoantibodies, derived principally from serum testing, is 98.1% (89.7–100%) and
100% (97.2–100%), respectively.10

Literature Review
We systematically appraised the literature to determine the prevalence of “positive” serum
testing for NMDAR IgG autoantibodies in patients with definite anti-NMDAR encephalitis
(Figure 1). The search was conducted using the PubMed and Embase databases with the
following search expression: (CSF AND SERUM) AND (NMDA OR NMDARE OR
NMDAR OR anti-NMDA OR anti-NMDAR OR anti-NMDARE OR N-methyl-D-aspartate
OR N-methyl-D-aspartate receptor encephalitis OR anti-N-methyl-D-aspartate receptor
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encephalitis OR NMDAR encephalitis OR Anti-NMDAR encephalitis). Articles and

abstracts published on or before March 30, 2019 were included regardless of the original
language of publication. All relevant works were independently reviewed by two study
authors (JAB and GSD), and clinical data were extracted concerning CSF and serum
autoantibody positivity and presenting symptoms and signs. Eleven articles included cases
where paired CSF and serum antibody tests were available from some cases but not others.
In these instances, only results from paired CSF and serum samples were included in the
analyses. Several articles reported findings from the same source population. In these cases,
results from the most recent publication were reported.4,7,11 Studies with individual
confidence interval estimates that fell outside the pooled confidence interval of the subgroup
were identified as outliers, and were excluded from meta-analyses. Individuals with CSF
testing negative for NMDAR IgG autoantibodies were assumed to be suffering from a form
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of autoimmune encephalitis other than anti-NMDAR encephalitis, and were excluded from
analyses. Studies meeting inclusion criteria were pooled using a random effects model.

The laboratory setting and methods used to evaluate NMDAR IgG autoantibodies were
extracted from published reports or, when not explicitly stated, from correspondence with
study authors. Laboratory setting was defined as local/regional or reference/research (i.e.,
laboratories actively supporting research into anti-NMDAR encephalitis). To be defined as a
research laboratory the testing institution was required to be ranked in the top half of

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rankings listed in the SCImago institutional ratings for health research (271 rankings
assigned as derived from the Scopus database).12 Granular data concerning pre-analytic
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variables (e.g., serum collection protocols; specimen handling and storage, and dilution)
were not routinely reported or collected. Testing approaches were defined as multi-modal
(e.g., evaluation with immunohistochemistry followed by cell-based assay) or unimodal
(e.g., use of cell-based assay alone). Complete data was available from 17/102 (17%)
published studies, which accounted for 432/612 (71%) of the total number of patients
sampled. The association between test site (local/regional versus reference/research) and
modality (multi-modal/unimodal), and odds of serum NMDAR IgG autoantibody detection
were measured with two-factor regression, incorporating studies with complete datasets.

No formal bias assessment was performed given that the majority of included studies were
retrospective case studies or case series, and therefore subject to a high degree of bias (Level
III or IV evidence according to the American Academy of Neurology Classification of
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Evidence Matrices for diagnostic or prognostic questions13). An unweighted Cohen’s Kappa

was computed, reflecting the overall agreement between raters with regard to a trichotomous
selection of inclusion, partial inclusion and exclusion of studies.

Statistical Analysis
Data were analyzed using R version 3.6.0 (The R Foundation, Vienna, Austria). Continuous
and categorical measures were compared using the Mann-Whitney U-test and Fisher’s exact
test, respectively. Statistical significance was defined as p<0.05, except for measures of
heterogeneity where statistical significance was defined as p<0.10. Confidence intervals for
concordance of detection of NMDAR IgG autoantibodies in serum versus CSF were
computed using a Clopper-Pearson exact technique. Inconsistency across studies was
computed using established methods.14,15 Pooled effects were computed using a random
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effects model given the apparent effect related heterogeneity initially on inspection of the
data. A McNemar test was used to compare autoantibody detection by testing using two
differing techniques in the established literature.

Results
Table 1 summarizes the demographic features, details of the clinical presentation and disease
course, and results of NMDAR IgG autoantibody testing in the 11 patients evaluated at our
center. The median age-at-symptom onset of anti-NMDAR encephalitis was 23 years (range,
15–52). The median time from first-reported symptom (or first symptom indicating relapse
in one patient) to NMDAR autoantibody testing was 28 days (range, 11–219; n=11) in CSF,
and 30 days (range, 10–218; n=7) in serum. In general, disease-defining symptoms and signs
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emerged in an ordered pattern (Figure 2), with 10/11 (91%) patients fulfilling clinical
criteria for ‘probable anti-NMDAR encephalitis’5 within a median of 19 days (range, 9–60)
from the onset of first symptoms. The remaining patient (patient 9) presented with agitation/
psychosis, decreased consciousness and seizures at the peak of his illness (day 31),
satisfying three of six proposed clinical criteria for the diagnosis of anti-NMDAR
encephalitis.5

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NMDAR IgG autoantibodies were detected within the CSF of all patients, establishing the
diagnosis of definite anti-NMDAR encephalitis.5 Paired serum samples were available from
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7/11 (64%) patients at the time of presentation. No clinically meaningful differences were
observed between patients with (n=7) and without paired serum samples (n=4) concerning
median age (28 years [18 – 52] vs 21.5 years [15 – 35]; p=0.51), the proportion of females
(0.71 vs 0.50; p=0.80), or the median time from symptom-onset to detection of NMDAR
IgG autoantibodies in the CSF (24 days [11 – 219] vs 29.5 days [17 – 57]; p=0.78).
NMDAR autoantibodies were not detected within the serum of any patient (0/6) tested at our
center. A third case (Case 5) was tested exclusively at a high-volume reference laboratory
(Mayo Clinic, Rochester, Minnesota, USA); NMDAR IgG autoantibodies were similarly
detected only in CSF (0/7 positive in paired serum samples).

Findings from our patients were compared with those from 102 publications reporting
results of autoantibody testing in CSF and serum from 663 patients who met criteria for
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definite anti-NMDAR encephalitis (i.e., all patients had clinical presentations consistent with
anti-NMDAR encephalitis with NMDAR IgG autoantibodies detected in CSF; Supplemental
Appendix 1). Inter-rater reliability was high (GSD and JAB, kappa = 0.95). Disagreement
arose over 5 cases considered by the reviewers to have anti-NMDAR encephalitis that had
positive autoantibodies in the serum but not in CSF.16–18 Ultimately, consensus was reached
to exclude these cases as absence of intrathecal NMDAR IgG autoantibodies was taken to
suggest another antibody-mediated or other cause of the clinical presentation (e.g. limbic
encephalitis, refractory seizure, etc.).

Serum NMDAR IgG autoantibody detection was 92% [95%CI: 88–95%] that of CSF with
the full dataset (n=612) and 82% [95%CI: 71–92%] in the dataset limited to studies with
complete information (n=432; Table 2, Figure 3). (The present study was excluded from this
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analysis as it was determined to be an outlier.) Substantial heterogeneity was observed in

data from the local/regional laboratory subgroup; mild-to-moderate heterogeneity was
observed in data from the reference/research laboratory group. Two-factor regression
analyses established reduced odds of serum NMDAR IgG autoantibody detection when
serum was tested using single approaches (e.g., cell-based assay without additional
technique; OR=0.20; 95%CI: 0.04–0.94; p=0.04), and when testing was performed within
local/regional laboratories (OR=0.20; 95%CI: 0.05–0.81; p=0.02).

Discussion
NMDAR IgG autoantibodies were detected in the CSF of all 11 patients with anti-NMDAR
encephalitis assessed at our center, but not in paired serum samples tested in seven patients.
Rates of serum detection (0/7) were lower-than-reported in the relevant literature. The use of
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a single test for antibodies and testing with local/regional laboratories were associated with
reduced odds of NMDAR IgG autoantibody detection in serum in published cases. These
findings raise important questions concerning the influence of testing methodology and
location on rates of serum NMDAR IgG autoantibody detection in patients with definite
anti-NMDAR encephalitis.

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The lower-than-expected rate of serum NMDAR IgG autoantibody detection at our center
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may reflect the small sample size and differences in our patient population compared to prior
published studies. Indeed, only one patient in our sample had a disease-associated ovarian
teratoma—a commonly associated neoplasm that may associate with higher serum NMDAR
IgG autoantibody titers.20 Alternatively, differences may be attributed to variation in
performance and interpretation of test results across centers—a hypothesis supported by the
high level of heterogeneity in serum/CSF test concordance observed across studies included
in the meta-analysis, and by the observation that the laboratory environment and modality of
testing (multimodal versus unimodal) influenced rates of serum autoantibody detection.

Additional factors may contribute to lower rates of serum antibody detection at clinical
centers like our own, including differences in initial sample collection (e.g., timing of
collection, equipment used for collection), handling and processing (e.g., sample dilution,
interval between sampling and testing, freeze/thaw cycles), testing, and interpretation of test
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results. In addition, academic and reference laboratories may adopt laboratory specific
practices intended to enhance assay performance, including the use of secondary or tertiary
diagnostic tests (e.g., brain immunohistochemistry, live cell-based assays) to increased
diagnostic accuracy.7,11,21 Indeed, the landmark study by Gresa-Arribas et al. suggested
improved rates of NMDAR IgG autoantibody detection when serum was tested using rat
brain immunohistochemistry in addition to cell-based assays with fixed or live NMDAR-
expressing cells.19 Although effective, these solutions increase the costs and complexity of
testing, detracting from the perceived advantages of in-house testing using commercially
avaible tests marketed for this purpose. Such solutions may be particularly challenging to
implement within lower-throughput laboratories, where the appeal of one-step commercial
testing may be greatest. These possibilities warrant further evaluation through a well-
designed systematic study considering the effects of experimental variation in sample
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collection, handling and processing, testing and interpretation of test results on serum
antibody detection.

Deciphering the factors that influence rates of NMDAR IgG autoantibody detection in serum
has important implications for research and clinical care. Anti-NMDAR encephalitis is a
potentially-treatable cause of first episode psychoses,22 post-partum psychoses,23,24
refractory mood disorders,25 unexplained behavioral changes,26–28 and neuroleptic
sensitivity.29,30 Accordingly, screening for serum anti-NMDAR IgG autoantibodies has been
performed in individuals with unexplained psychiatric presentations in whom obtaining CSF
may present undue challenges.2,9,22 However, building evidence suggests that the accuracy
of serum testing alone is inadequate.7 Indeed, at least 1 of 13 patients with definite anti-
NMDAR encephalitis included in our meta-analyses may have been misdiagnosed if relying
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on serum testing alone. This clinical practice point is even more relevant when evaluating
patients with atypical clinical presentations (e.g. patients with first-episode psychoses), in
whom the identification of NMDAR IgG autoantibodies in serum alone may fail to inform
the clinical diagnoses.9 Taken together, these findings reinforce the need to test for NMDAR
IgG autoantibodies in the CSF of patients with suspected anti-NMDAR encephalitis.

Several barriers may impede CSF testing in patients with prominent psychiatric signs,
including the need to obtain informed consent in decisionally-impaired patients, and

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practical challenges associated with performing a diagnostic lumbar puncture outside of

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traditional inpatient settings. It is important to circumvent these barriers to ensure the most
accurate evaluation, and to deliver the best possible care to at-risk patients. This may
necessitate further collaboration between neurological and psychiatric service providers in
outpatient and inpatient settings. On the neurology service, where diagnostic lumbar
punctures are routine and can be safely performed with minimal pain or risk to the patient,
simultaneous screening of CSF and serum samples for disease-associated autoantibodies is
recommended in patients with suspected autoimmune encephalitis to promote early
detection of disease-associated autoantibodies. This strategy allows for early treatment,
when appropriate, recognizing that time-to-treatment is consistently associated with poorer
long-term outcomes in retrospective case-series of autoimmune encephalitis patients.
4,11,31,32 This recommendation also acknowledges the need to screen for other disease-

associated autoantibodies that may account for the clinical presentation, including
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autoantibodies that are optimally detected in serum (e.g., leucine-rich gliomainactivated

protein-1 [LGI1] or contactin-associated protein 2 [CASPR2] autoantibodies33,34).

This study is subject to several limitations. Although the patients included in this study were
prospectively enrolled and longitudinally followed, study protocols did not include banking
of serum. Thus, it was not possible to evaluate additional aliquots of serum from enrolled
patients using other methods or techniques at other centers. We acknowledge that local test
results may have accurately reflected patient serum antibody status (“true negative”). This
finding is supported by lack of autoantibody detection on selected samples that were also
evaluated at a reference laboratory (i.e., patients 4, 5 and 7). Indeed, persistently
seronegative cases of anti-NMDAR encephalitis are well recognized,35,36 suggesting that
patient- and/or disease-specific factors may influence the detection of NMDAR IgG
autoantibodies in serum. It is also plausible that further testing on serum samples utilizing
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additional techniques (e.g., immunohistochemistry, live cell-based assays7) may have

identified NMDAR IgG autoantibodies at clinically relevant levels (in which case our
findings would be regarded as “false negatives”). Future studies are needed to systematically
evaluate the effect of pre-analytic variation in sample collection, handling and processing on
serum antibody detection. It is particularly imperative that these studies bank serum and CSF
samples from patients with definite anti-NMDAR encephalitis, permitting samples to be
evaluated using more than one analytic method, in more than one environment (local/
regional and research/academic laboratories). The findings presented here may be used to
justify the effort and investment required to facilitate such rigorous follow-up studies in
larger numbers of patients.

Conclusions
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Commercial kits are available that allow NMDAR IgG autoantibodies to be measured in
local laboratories. However, analysis of paired CSF and serum samples from patients with
definite anti-NMDAR encephalitis presenting to our center suggests that commercial kits run
according to manufacturer’s specifications in exemplar clinical laboratories may yield lower-
than-expected rates of NMDAR IgG autoantibody detection in serum. Testing within local/
regional laboratories and the use of single test modalities associated with reduced odds of
serum NMDAR IgG autoantibody detection in the extant literature. These findings

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emphasize the need for caution when interpreting serum NMDAR IgG autoantibody test
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results, and the need for future studies evaluating the factors that influence autoantibody
detection rates across centers. Clinicians should continue to prioritize testing for NMDAR
IgG autoantibodies in CSF from patients with suspected anti-NMDAR encephalitis.

Acknowledgments:
The authors thank Dr. Ann Gronowski for helpful comments concerning an earlier version of this work. The authors
remain grateful to the patients and family members who made this work possible.

Funding

This study was made possible by support from the American Brain Foundation (Clinical Research Training
Fellowship, GSD).

Conflict of Interest
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Dr. Brooks is supported by fellowship funding from the Canadian Network of MS Clinics (including support from
Biogen Idec Canada, EMD Serono, Sanofi Genzyme, Novartis Pharmaceuticals Canada Inc., Hoffmann-La Roche
and Teva Canada Innovation). Dr. Yarbrough declares no conflicts of interest. Dr. Bucelli receives an annual gift
from a patient’s family for Parsonage-Turner research, has served on an advisory board for MT Pharma, and has
equity in Neuroquestions, LLC. Dr. Day is supported by funding from the NIH/NIA (K23AG064029), is involved in
research supported by an in-kind gift of radiopharmaceuticals from Avid Radiopharmaceuticals, serves as a topic
editor for DynaMED (EBSCO Health), and holds stocks (>$10,000) in ANI Pharmaceuticals (a generic
pharmaceutical company). Dr. Day serves as the clinical director of the Anti-NMDA Receptor Encephalitis
Foundation (no compensation provided); the Foundation is supported by private donations.

Appendix
Appendix 1.

Complete results of literature review including all publications that presented results of
serum and CSF NMDAR IgG autoantibody testing in patients with definite anti-NMDAR
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encephalitis.

NMDAR antibody testing

Reference/Testing Location Paired Age (median Serum +: Technique/Test
(SCImago Rank of 271) samples (n) [range]) M:F CSF + Site
Gresa-Arribas et al., 20141 250 unknown unknown 232:250 2/R
University of Pennsylvania (14)
Wang et al., 20152 Peking Union 43 23 [9 – 39] 19:24 27:43 1/L
Medical College Hospital (166)
Saito et al., 20173 Kanazawa 37 unknown unknown 17:37 1/L
University Hospital (192)
Aungsumart et al., 20194 Prasat 31 19 [IQR: 15 – 12:19 21:31 2/L
Neurological Institute (NL) 31]
Ding et al., 20185 Nanfang 24 Mean: 40 (SD: 10:14 18:24 1/L
Hospital (158) 18)
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Ge et al., 20166 20 unknown unknown 20:20 U/U

Erazo et al, 20167 University of 13 6 [1 – 16] 9:4 13:13 U/R
Pennsylvania (14)
Maat et al, 20138 Erasmus 12:15 25 [5 – 56] 2:13 9:12 (0) 1/R★
Medical Center (24)
Mahadevan et al., 20169 N/ 11 unknown unknown 11:11 1/L
MHANS (NL)
Libaet al.,201610 9† 13 [7 – 26] 1:8 9:9 1 / U�

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NMDAR antibody testing

Reference/Testing Location Paired Age (median Serum +: Technique/Test
(SCImago Rank of 271) samples (n) [range]) M:F CSF + Site
Ramirez et al, 201511 San Luis 8 unknown unknown 8:8 U/L
Potosi City Reference Hospitals
(NL)
Holzereta,, 201312 7 22 [17 – 58] 1:6 7:7 U/U
Gao et al, 201413 7 Female: [19 – 2:5 6:7 U/U
31], Male: 52
[47 – 58]
Candia et al., 201514 6 [5 – 16] 0:6 6:6 U / U*
Pruss et al., 201015 6 22.5 [18 – 31] 0:6 5:6 2 / U�
Song et al., 201316 5:6 unknown unknown 5:5 (0) U / U�
Zhou et al., 201417 5 unknown unknown 5:5 U/U
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Suhs et al., 201518

Hannover 5:7† [23 – 57] 0:7 4:5 (1) 1/L★
Medical School (NL)
Zoccarato et al., 201719 4 [7 – 27] 3:1 4:4 1/U
Kataoka et al., 201720
University 3 29 [18 – 46] 1:2 3:3 2/R★
of Pennsylvania (14)
Bashiri et al., 20171 3 [10 mo - 5] 0:3 3:3 U / U�
Bastos et al., 2032 3 [13 – 34] 0:3 3:3 U/U
Gastaidi et al., 201623 Oxford 3:5 unknown unknown 3:3 2/R★
University Hospitals (68)
Nosadini et al., 201324 3 unknown unknown 3:3 1/U
Su et al., 201525 3 unknown 2:1 3:3 U / U�
Zandi et al., 201526 Oxford 5:8 unknown unknown 5:5 (3) 2/R★
University Hospitals (68)
Wright et al., 201527 2 2 [2] unknown 2:2 U/U
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Sankhyan et al., 201528 2 6 [4 – 8] 1:1 2:2 U/U

Aung et al., 201529 2 23 [23 – 23] 1:1 2:2 U/U
Aiexopouios et al., 201830
Athens 5:5 29 [9 mo, 58] 0:2 3:3 (1) 1/L
University Hospital (202)
Qin et al., 201731 2:4 36 [33 – 39] 2:0 2:2 U / U�
Qiu et al., 2018 32 2:4 49 [31 – 67] 0:2 2:2 U/U
Kitada et al. , 201133 2 54 [38, 71] 1:1 2:2 2/U
Tuzun et al. 2015 34 2 63 [62 – 64] 2:0 2:2 U/U
Gaunt et al., 201735 1 7 mo 0:1 1:1 U/U
Crowe et al., 2014 36 1 16 mo 0:1 1:1 U/U
Bektas et al., 2013 37 1 19 mo 0:1 1:1 U / U�
Iyer et al., 2014 38 1 3 1:0 1:1 U/U
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Deiva et al. 2014 39 1 4 0:1 1:1 U / U�

Barros et al., 2014 Oxford40 1 7 1:0 1:1 2/R
University Hospitals (68)
Lee et a,, 201641 1 7 0:1 1:1 U / U�
Tamma et al., 201142 1 7 1:0 1:1 U/U
Mitani et al., 201343 1 8 1:0 1:1 U / U�
Caietal.,201844Peking Union 1 9 0:1 1:1 U / L�
Medical College Hospital (166)

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NMDAR antibody testing

Reference/Testing Location Paired Age (median Serum +: Technique/Test
(SCImago Rank of 271) samples (n) [range]) M:F CSF + Site
Korenke et al., 201345 1 12 1:0 1:1 U/U
Eiango et al., 201646 1 13 0:1 1:1 U/U
Babiker et al., 201547 1 15 0:1 1:1 U/U
Kevere et al. 201548 1 15 0:1 1:1 U/U
Rangseekajee et al., 201549 1 15 0:1 1:1 U/U
Ubodet al., 201650 1 15 1:0 1:1 U/U
Wang et al., 201651 1 15 0:1 1:1 U / U�
Dasyam et al., 201452 1 17 0:1 1:1 U/U
Nastase et al. 201253 1 18 0:1 1:1 U/U
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Pereira, et al. 201654 1 18 0:1 1:1 U/U

Sousa et al. 201455 1 18 0:1 1:1 U/U
Gutierrez-Zuniga et al., 201656 1 19 0:1 1:1 U/U
Shimoyama et al., 2016 57 1 19 0:1 1:1 U/U
Fontao et al., 2016 58 1 20 1:0 1:1 U/U
Liang et al., 2016 59 1 20 0:1 1:1 U/U
Wang et al. 2018 60 1 20 0:1 1:1 U/U
Algra et al. 2014 61 1 21 0:1 1:1 U/U
Barrozo et al., 201762 1 21 1:0 1:1 U/U
Fauzi et al., 201763 Hospital Kuala 1 21 0:1 1:1 1/L★
Lumpur (NL)
Saiehi et al. 2018 64 1 21 0:1 1:1 U/U
Tachibana et al., 2010 65 1 21 0:1 1:1 1 / U�
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Vansia et al., 2016 66 1 22 0:1 1:1 U/U

Amado-Rodriguez et al., 2018 67 1 23 0:1 1:1 U / U�
Rehder et al. 2016 68 1 24 0:1 1:1 U/U
Grewai et al. 2018 69 1 25 0:1 1:1 U/U
Anadani et al. 2014 70 1 26 1:0 1:1 U/U
Shahani et al., 2014 71 1 26 0:1 1:1 U/U
Shahbeigi et al., 2014 72 1:3 27 0:1 1:1 U/U
Kaneko et al., 2015 73 1 28 0:1 1:1 U/U
O’Donnell et al., 2017 74 1 28 1:0 1:1 U/U
Li et al., 2018 75 1 29 0:1 1:1 U / U�
Cesarini et al., 2018 76 1 30 0:1 1:1 U/U
Hegen et al., 2016 77 1 31 0:1 1:1 U / U�
Author Manuscript

Takahashi et al., 2013 78 1 31 0:1 1:1 U/U

Yamamoto et al., 2013 79 1 31 0:1 1:1 1/U
Bashir et al. 201780 1 32 0:1 1:1 U/U
Chourasia et al., 2018 81 1 32 0:1 1:1 U / U�
Munoz et al., 2015 82 1 32 0:1 1:1 U/U
Park et al., 2018 83 1 33 0:1 1:1 U/U
Hur et al., 2015 84 1 36 0:1 1:1 U : U�

Can J Neurol Sci. Author manuscript; available in PMC 2021 March 30.
 Brooks et al. Page 11
Author Manuscript

NMDAR antibody testing

Reference/Testing Location Paired Age (median Serum +: Technique/Test
(SCImago Rank of 271) samples (n) [range]) M:F CSF + Site
Lineberry et al., 2013 85 1 38 0:1 1:1 U/U
Thomas et al., 2012 86 1 39 0:1 1:1 U/U
Wagner et al., 2018 87 1 40 1:0 1:1 U/U
Hung et al., 201788 1 44 1:0 1:1 U/U
Rojc et al., 2019 89 1 47 1:0 1:1 U/U
Zoccarato et al., 2013 90 1 50 0:1 1:1 U/U
Power et al., 201791 1 52 0:1 1:1 U/U
Zhou et al., 201892 Euroimmune 1 54 1:0 1:1 1/R
China (REF)
Guan et al., 201593 Peking Union 1 59 0:1 1:1 1/L
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Medical College Hospital (166)

Jeraiby et al., 2016 94 1 62 0:1 1:1 U / U�
Chenet al., 2014 95 1 unknown 0:1 1:1 U/U
Kelleher et al , 2015 96 1:4 Female: 55, 3:1 1:1 1/U
Male: Mean:
48 (SD: 16.3)
Kukreti et al., 201597 1 unknown 0:1 1:1 U / U�
Mohammad et al. ,2013 98 1 unknown 1:0 1:1 U/U
Zhang et al., 201799 1 18 0:1 0:1 U/U
Orengo et al., 2015 Mayo100 1 29 0:1 0:1 1/R★
Clinic (7)/ARUP (REF)
Berth et al., 2017101 1 53 1:0 0:1 U/U
Finke et al., 2014 102 1 67 1:0 0:1 1 / U�
Summary (Random Effects) [7 mo – 71] 97:222 532:612
Author Manuscript

With the authors/citation is listed the principal testing site/affiliated institution, and associated SCImago rank103 (where
available). When relevant, the “n” for patients with paired samples indicates both the number of patients with paired CSF
and serum samples (numerator), as a proportion of the total cases presented (denominator). The NMDAR autoantibody
testing reports number of serum positive (numerator) compared to number of CSF positive (denominator) results. The
number of patients who demonstrated positivity in serum but not CSF are included in parentheses (excluded from
analyses). The median age and age range of patients presented in each study is listed unless otherwise stated. Time between
CSF and serum testing, and severity of illness were not uniformly reported. No adverse events were reported secondary to
blood draw or lumbar puncture. 1: Single modality testing; 2: Multimodal testing (≥2 modalities used); ARUP: Associated
Regional University Pathologists, Inc.; CSF: Cerebrospinal fluid; L: Testing performed at a local/regional test site; NL: The
test site was not listed in the available rankings; R: Testing performed at reference/research test site; REF: The testing
center was a reference center
�:
Data clarification requested but not provided;
★:
Data clarification requested and provided;
†:
Studies where more than one paired sample was obtained per patient.
Author Manuscript

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Figure 1.
Flow diagram depicting results of the meta-analysis. See Methods for search terms. Search
results were reviewed and articles excluded if they focused on animal studies, diseases other
than anti-NMDAR encephalitis, drug treatment without patient data, or if the article was
unavailable for review or was a reference article (no patient data). Articles were also
excluded if paired CSF and serum antibody test results were not reported, or if antibodies
other than NMDAR IgG autoantibodies were reported. Relevant data was extracted from the
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108 resultant articles and used to inform results. Ab: antibody; CSF: cerebrospinal fluid.
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 Brooks et al. Page 24
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Figure 2.
Box plot depicting the median number of days from the onset of first symptom(s), to the
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emergence of symptoms and signs typical of anti-NMDAR encephalitis.

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 Brooks et al. Page 25
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Figure 3.
Forest plot with estimates of serum concordance with cerebrospinal fluid testing (diamonds)
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for NMDAR autoantibodies and 95% confidence intervals (solid bars), ordered by
descending sample size. Studies with a sample size <5 where the testing performed was not
stated are not displayed.
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 Brooks et al. Page 26

Table 1.

Demographic features, details of clinical presentation and course, and results of diagnostic testing for 11 anti-
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NMDAR encephalitis patients evaluated at our center.

NMDAR IgG antibody test results

Age, Additional diagnostic
Case Symptoms/Signs In-House Reference Treatment
M/F testing
CSF Serum CSF Serum
Oral steroids,
EEG: AC
1. A/P, Sz + (Day + (Day IVMP, IVIg,
1 20F NA NA MRI Brain: ANS
2. Dk, Da 57) 57) PLEX,
Tumor: none
rituximab

EEG: AC
1. A/P
+ (Day + (Day MRI Brain: IVMP, IVIg,
2 23F 2. SD − (Day 30) NA
32) 32) Nm Tumor: PLEX
3. LOC, Dk, Da
Mature ovarian teratoma

1. LOC, SD EEG: ANS

+ (Day + (Day
3 35F 2. A/P NA NA MRI Brain: Nm IVMP, IVIg
31) 31)
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3. Da Tumor: none

1. LOC, Sz EEG: ANS

+ (Day − (Day IVMP, PLEX,
4 31M 2. A/P NA − (Day 32) MRI Brain: Nm
24) 32) IVIg
3. Da Tumor: none

EEG: ANS
1. A/P + (Day − (Day IVMP, PLEX,
5 18F NA NA MRI Brain: Nm
2. LOC, Dk, Da 23) 23) rituximab
Tumor: none

1. SD EEG: Nm
+ (Day
6 15M 2. LOC NA NA NA MRI Brain: IVMP
28)
3. A/P, Dk Nm Tumor: none

EEG: ANS
1. Dk + (Day − (Day
7 20M NA − (Day 10) MRI Brain: ANS IVMP, IVIg
2. SD, A/P, Sz 11) 10)
Tumor: none

1. A/P
EEG: ANS IVMP, IVIg,
2. Dk + (Day
8 32F − (Day 31) NA NA MRI Brain: Nm PLEX,
3. LOC 32)
Tumor: none rituximab
4. SD, Sz, Da
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EEG: ANS
1. A/P, LOC + (Day IVMP, IVIg,
9 23M NA NA NA MRI Brain: AC
2. Sz 17) rituximab
Tumor: none

1. SD
2. LOC EEG: ANS
+ (Day − (Day + (Day Oral steroid,
10 52F 3. A/P NA MRI Brain: ANS
219) 218) 219) IVMP, IVIg
4. Dk Tumor: none
5. Sz

1. Sz, Da EEG: AC
+ (Day IVMP, PLEX,
11 28F 2. SD, A/P − (Day 11) NA NA MRI: Nm
13) rituximab
3. Dk, LOC Tumor: none

Symptoms are ordered by onset. Timing of CSF and serum testing is presented relative to the day of symptom onset. MRI and EEG findings were
either normal (Nm: indicating no pathological abnormality), abnormal-nonspecific (ANS: indicating abnormalities that are not specific for anti-
NMDAR encephalitis, including non-specific FLAIR signal changes on MRI, and slowing on EEG) or abnormal-consistent (AC: indicating
abnormalities that are consistent with anti-NMDAR encephalitis, such as mesial temporal lobe signal changes with or without extension into
adjacent limbic structures on MRI, and delta-brush on EEG). No adverse events were attributed to blood draw or lumbar puncture. +: Positive
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result; -: Negative result; A/P: Agitation / Psychosis; CSF: Cerebrospinal fluid; Da: dysautonomia; Dk: Dyskinesia; EEG: Electroencephalogram;
FLAIR: T2-fluid-attenuated inversion recovery; LOC: Altered level of consciousness; MRI: Magnetic resonance image; IVMP: Intravenous
methylprednisolone; IVIg: Intravenous immunoglobulin; PLEX: Plasmapheresis / plasma exchange; SD: speech dysfunction; Sz: Seizure.

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 Brooks et al. Page 27

Table 2.

Results of literature review including cases with definite anti-NMDAR encephalitis for whom complete data
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concerning results of autoantibody testing in serum and CSF were available.

NMDAR antibody testing

Reference Patients with Paired samples
(n) Age (median [range]) M:F Serum +: CSF + Technique/Test Site

Gresa-Arribas et al., 20147 250 unknown unknown 232:250 2/R

Wang et al., 201537 43 23 [9 – 39] 19:24 27:43 1/L

Salto et al., 201738 37 unknown unknown 17:37 1/L

Aungsumart et al., 201939 31 19 [IQR: 15 – 31] 12:19 21:31 2/L

Ding et al., 201840 24 Mean: 40 (SD: 18) 10:14 18:24 1/L

Maat et al., 201316 12:15 25 [5 – 56] 2:13 9:12 (0) 1/R

Mahadevan et al., 201641 11 unknown unknown 11:11 1/L

Suhs et al., 201517 5:7 [23 – 57] 0:7 4:5 (1) 1/L
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Kataoka et al., 201742 3 29 [18 – 46] 1:2 3:3 2/R

Gastaldi et al., 201643 3:5 unknown unknown 3:3 2/R

Zandi et al., 201520 5:8 unknown unknown 5:5 (3) 2/R

Alexopoulos et al., 201844 5:5 29 [9 mo, 58] 0:3 3:3 1/L

Barros et al., 201445 1 7 1:0 1:1 2/R

Fauzi et al., 201746 1 21 0:1 1:1 1/L

Zhou et al., 201847 1 54 1:0 1:1 1/R

Orengo et al., 201548 1 29 0:1 0:1 1/R

Guan et al., 201548 1 59 0:1 1:1 1/L

When relevant, the “n” for patients with paired samples indicates both the number of patients with paired CSF and serum samples (numerator), as a
proportion of the total cases presented (denominator). The NMDAR autoantibody testing reports number of serum positive (numerator) compared
to number of CSF positive (denominator) results. The number of patients who demonstrated positivity in serum but not CSF are included in
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parentheses (excluded from analyses). The median age and age range of patients presented in each study is listed unless otherwise stated. Time
between CSF and serum testing, and severity of illness were not uniformly reported. No adverse events were reported secondary to blood draw or
lumbar puncture. 1: Single modality testing; 2: Multimodal testing (≥2 modalities used); CSF: Cerebrospinal fluid; L: Testing performed at local/
regional test site; R: Testing performed at reference/research test site
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