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Abstract

Objective

We sought to validate methods for detection and confirmation of GABAA receptor (R)-IgG and clinically characterize seropositive cases.

Methods

Archived serum and CSF specimens (185 total) suspected to harbor GABAAR-IgG were evaluated by indirect immunofluorescence assay (IFA). Twenty-six specimens from 19 patients appeared suspicious for GABAAR–IgG positivity by IFA, based on prior reports and comparison with commercial GABAAR antibody staining. Aliquots of those specimens were tested at the University of Oxford, United Kingdom, and Euroimmun, Lubeck, Germany, for GABAAR-IgG by cell-based assays (CBAs) using HEK293-indicator cells transfected with plasmids encoding different GABAAR subunits.

Results

Eight specimens (of 26 tested; 4 serums, 4 CSFs) from 5 patients were confirmed by CBA to be GABAAR-IgG positive. Patient IgGs were always reactive with α1β3 GABAAR subunits. One more patient was identified clinically after this validation study. Median age for the 6 patients at serologic diagnosis was 44 years (range, 1–71 years), and 4 of them were male. Among the 4 for whom clinical information was available (2 treated by the authors), all had encephalitis and antiepileptic drug refractory seizures. Three out of 4 patients treated with a combination of immunotherapies had good outcomes. The fourth, recognized to have an autoimmune cause late in the clinical course, had severe permanent neurologic sequelae and brain atrophy.

Conclusions

Though not as common as NMDA-R encephalitis, GABAAR encephalitis generally has a characteristic clinical-radiologic presentation and is treatable, making accurate laboratory diagnosis critical.
Diagnostic certainty is often lacking in neural-IgG antibody seronegative autoimmune encephalitis.1 Novel disease-specific IgG biomarker characterization enhances diagnostic sensitivity. γ-aminobutyric acid (GABAA) receptor (R) encephalitis is an immunotherapy responsive, presumably IgG-mediated, disorder. Patient IgGs target the α1 and β3 subunits of the pentameric GABAAR (nicotinic acetylcholine receptor superfamily of ligand-gated ion channels, arranged as γ-β-α-β-α).2,3 This disorder appears to be less common than NMDA-R encephalitis (the largest reported series of GABAAR encephalitis comprised 26 patients, with 11 children).3,4 Typically, GABAAR encephalitis presented with refractory status epilepticus, or epilepsia partialis continua, with multifocal MRI lesions in the cerebral cortex and subcortex. We sought archival cases in the Mayo Clinic Neuroimmunology Laboratory database, based on recorded patterns observed by tissue-based indirect immunofluorescence assay (IFA), and characterized those patterns in detail. Findings were confirmed by cell-based assays (CBAs) in 2 international research and diagnostic laboratories (the University of Oxford, UK, and Euroimmun, Lubeck, Germany).

Methods

Standard protocol approvals, registrations, and patient consents

The Mayo Clinic institutional review board approved this study (IRB # 08–006647).

Laboratory methods

Archived specimens were sera (116) and CSF specimens (CSFs, 69) from 154 patients referred to the Mayo Clinic Neuroimmunology Laboratory for service evaluation (2011–2018). Those specimens had stained murine brain synapses, by IFA, in a pattern potentially compatible with GABAAR-IgG (appendix e-1, links.lww.com/NXI/A103).3 On retesting by IFA, 26 of those specimens, from 19 patients, were scored as having moderate (18) or high (8) likelihood of GABAAR–IgG positivity. Aliquots (serum only, 6; CSF only, 6; both serum and CSF, 7) were tested at the University of Oxford, United Kingdom, and Euroimmun, Lubeck, Germany, for GABAAR-IgG by CBAs, appendix e-1.

Data availability

All data pertaining to this article are contained within or published as online supplement.

Results

Eight of 26 specimens from 5 patients were confirmed by CBA to be GABAAR-IgG positive. Four of those 5 patients' specimens had been scored as high likelihood by IFA. IgG staining was most prominent in synapses of the hippocampus, dentate gyrus, thalamus, and cerebellar granular layer (figure 1). Purkinje cells (figure 1) and myenteric plexus (not shown) did not stain.
Figure 1 GABAA receptor (R)-IgG staining characteristics by tissue-based IFA
GABAAR-IgG produces intense synaptic staining of the hippocampus (Hi) and dentate gyrus (Dg), (A) cortex (Cx), (B) and thalamus (Th), (C) which relatively spares the CA3 hippocampal region (arrows). Cerebellar synapses more robustly stain in the granular layer (GL) than molecular layer (ML), D. Purkinje cell (PC) staining is absent. Scale bar = 100 μm.
For one patient, serum only was positive (CSF unavailable); for another, CSF only was positive (serum unavailable), and for 3 patients both serum and CSF were positive (100%). Inter-CBA testing was concordant for all specimens except for one CSF (negative in the Euroimmun Lab and positive in the Oxford Lab); the paired serum was positive in both laboratories. All positive specimens were reactive with α1β3 GABAAR subunits. None were reactive with γ2 subunit only.
One more patient (number 6, table) was evaluated for encephalitis at Mayo Clinic after the serologic study was completed, and was confirmed to be GABAAR-IgG-positive at the University of Barcelona. Among the 6 patients, the median age at serologic diagnosis was 44 years (range, 1–71 years), and 4 of them were male (table). Medical histories were available for 4. All had encephalitis with antiepileptic drug refractory seizures. One had neoplasia (thymoma). Three patients treated with immunotherapies had good outcomes.
Table Characteristics of 4 GABAAR encephalitis patients
A fourth patient, a one-year-old child, was recognized late to have an autoimmune cause for seizures and had severe permanent neurologic sequelae.

Illustrative cases

Case 3

A 59-year-old man, previously healthy, had seizures consisting of acidic-metallic taste and lip-smacking. Over the next week, the seizure frequency increased, and he developed amnestic symptoms and dysphasia. He had a seizure characterized by right arm and leg tonic-clonic movements. MRI brain showed nonenhancing, confluent T2 hyperintense left medial temporal lobe lesions, and 2 smaller juxtacortical lesions (figure 2A). CSF was initially bland, but 3 weeks into the illness contained 7 white blood cells (WBCs) per μL (normal value, ≤ 5; 86% lymphocytes) and elevated total protein (59 mg/dL; normal, < 35 mg/dL). CT chest revealed an anterior mediastinal mass; thymoma was confirmed at surgical removal. Intravenous immune globulin (IVIg) (2 g/kg divided over 3 days), then IV methylprednisolone (1,000 mg daily for 5 days), was followed by substantial but incomplete cognitive improvements. Improvement continued after thymectomy. Confusion, seizures, and paranoia developed 3 months after initial presentation. CSF examination revealed only elevated total protein (69 mg/dL). Head MRI demonstrated improvement in some T2 lesions, complete resolution of others, and new lesions in bilateral temporal and frontal lobes (nonenhancing, figure 2B). No further improvement followed IVIg (2 g/kg). However, substantial clinical improvement and long-term seizure cessation accompanied IV methylprednisolone treatment (1,000 mg/d for 5 days) followed by plasma exchange. After treatment, neuropsychological testing demonstrated below average performance in immediate verbal recall and mild problems with confrontation naming, verbal agility, and semantic fluency. Brain MRI showed significant improvement of some lesions, but persistence of others, with temporal lobe atrophy (figure 2C). After 6 months of symptoms, he received rituximab 1,000 mg IV, 2 doses, 2 weeks apart, while continuing a prednisone taper. At 8 months, he was independent in activities of daily living but was not working and needed help managing finances.
Figure 2 Serial axial brain images from patients 3 (A–C, axial T2 FLAIR) and 4 (D, axial T2 FLAIR and. PET)
(A) At presentation, patient 3 had a large confluent lesion in the left mesial temporal lobe and hippocampus (including hippocampal tail) and adjacent orbital frontal cortex, and 2 smaller cortically based FLAIR hyperintense lesions in the right medial posterior frontal and right medial occipital lobes and left insula. Lesions were hypointense on T1 and had no abnormal enhancement following the administration of gadolinium (not shown). (B) Three months later, repeat MRI demonstrated improvement of earlier abnormalities and new juxta-cortical FLAIR hyperintense lesions in the bilateral frontal and temporal lobes, without abnormal enhancement (not shown). (C) MRI repeated 6 months after initial presentation demonstrated interval improvement in prior lesions and residual T2 hyperintensity within bilateral medial temporal lobes, and asymmetric bilateral temporal lobe atrophy, corresponding to prior regions of T2 hyperintensity. For patient 4, 5 years into her illness, MRI (D.a and D.c) demonstrated cortical and subcortical hyperintensities. FDG/PET-CT hypermetabolism (red and blue arrows, D.b and D.d) occurred in the presence (red arrow, D.a) and absence (blue arrow, D.c) of MRI lesions. (A) FLAIR cortical hyperintensity (purple arrow, D.a) without FDG/PET correlate is also indicated (purple arrow, D.b). Green arrow indicates the patient's biopsy site. FLAIR = fluid-attenuated inversion recovery.

Case 4

A 55-year-old woman with a history of Hashimoto thyroiditis, rheumatoid arthritis, Sjogren syndrome, and type 1 diabetes, developed new onset seizures with focal neurologic signs (left-sided weakness). CSF contained 23 WBCs/μL (lymphocyte predominant) and normal protein. MRI demonstrated multifocal juxtacortical and subcortical T2 hyperintense lesions, without gadolinium enhancement. For the next 5 years, episodic cognitive impairment continued with recurrence of antiepileptic drug-refractory seizures. Worsening seizures were accompanied by waxing and waning T2-hyperintense MRI lesions, nonenhancing. Symptoms and radiologic abnormalities resolved following treatment with IV methylprednisolone and plasma exchange. Left frontal lobe biopsy was nondiagnostic. The patient had coexisting glutamic acid decarboxylase (GAD) 65 autoimmunity (serum GAD65-IgG, 280 nmol/L; CSF, 0.08 nmol/L; normal value, ≤ 0.02). No neoplasm was identified despite repeated whole-body CT scans over the course of 5 years. PET-CT scan of brain revealed hypermetabolic lesions, some co-localizing with T2-hyperintense lesions in the MRI, and others not (figure 2D). Neurologic examination 2 months after her most recent relapse demonstrated mild difficulties with construction and calculation. Rituximab was recommended for relapse prevention.

Discussion

We identified GABAAR encephalitis cases by IFA and required CBA to confirm. Consistent with prior reports, this approach did not yield isolated γ2 subunit-specific positivity.3 GABAAR encephalitis occurred across the age range and in both sexes.3 Antiepileptic drug-refractory seizures, other encephalitic symptoms, and abnormalities on brain MRI (multifocal, non–diffusion-restricting, nonenhancing, medium-to-large sized cortical, juxtacortical and subcortical lesions) or PET should prompt testing for GABAAR encephalitis.2 Brain MRI may occasionally be normal.3
Search for thymoma should be undertaken in adults, and others (diverse carcinomas and myeloma) should be considered.3 Patients with thymoma, with and without encephalitis, usually have multiple autoantibodies detectable in characteristic profiles dominated by nicotinic acetylcholine receptor superfamily antigenic specificities.5 In some encephalitis cases, GABAAR-IgG may prove the only serologic clue to an autoimmune pathogenesis. Other thymoma-pertinent IgG specificities encountered in autoimmune encephalitis include α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid-R, muscle-type and ganglionic (α3)-type acetylcholine receptors, striational, GAD65, leucine-rich glioma inactivated 1, and contactin associated protein 2.5,6
Both patients we reported in detail were treated promptly with corticosteroids and plasma exchange, and had robust improvements, but relapsed upon treatment withdrawal. In contrast, an infant recognized late to have autoimmune encephalitis had cerebral atrophy and severe permanent neurologic sequelae. At the current time, the Euroimmun and Oxford laboratories identify 5–10 cases of autoimmune GABAAR encephalitis per year. The number of cases identified prospectively at Mayo Clinic remains to be determined. A prospective study will compare the sensitivity and specificity of different specimen types (serum and CSF) and assays (CBA and IFA). Low titers of serum antibodies detected by CBA only appear less clinically specific.2
In summary, GABAAR encephalitis should be considered in patients with encephalopathy and seizures (especially those refractory to antiepileptic drugs) with multifocal brain lesions on imaging. Prompt immunotherapy and neoplasm search should follow.

Glossary

CBA
cell-based assay
GABAA
γ aminobutyric acid
GAD
glutamic acid decarboxylase
IFA
immunofluorescence assay
IVIg
intravenous immune globulin
WBC
white blood cell

Footnote

Editorial, page e554

References

1.
Hacohen Y, Wright S, Waters P, et al. Paediatric autoimmune encephalopathies: clinical features, laboratory investigations and outcomes in patients with or without antibodies to known central nervous system autoantigens. J Neurol Neurosurg Psychiatry 2013;84:748–755.
2.
Petit-Pedrol M, Armangue T, Peng X, et al. Encephalitis with refractory seizures, status epilepticus, and antibodies to the GABAA receptor: a case series, characterisation of the antigen, and analysis of the effects of antibodies. Lancet Neurol 2014;13:276–286.
3.
Spatola M, Petit-Pedrol M, Simabukuro MM, et al. Investigations in GABAA receptor antibody-associated encephalitis. Neurology 2017;88:1012–1020.
4.
Dalmau J, Lancaster E, Martinez-Hernandez E, Rosenfeld MR, Balice-Gordon R. Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol 2011;10:63–74.
5.
Zekeridou A, McKeon A, Lennon VA. Frequency of synaptic autoantibody accompaniments and neurological manifestations of thymoma. JAMA Neurol 2016;73:853–859.
6.
Simabukuro MM, Petit-Pedrol M, Castro LH, et al. GABAA receptor and LGI1 antibody encephalitis in a patient with thymoma. Neurol Neuroimmunol Neuroinflamm 2015;2:e73.

Information & Authors

Information

Published In

Neurology® Neuroimmunology & Neuroinflammation
Volume 6Number 3May 2019
PubMed: 31119187

Publication History

Received: December 28, 2018
Accepted: February 14, 2019
Published online: April 4, 2019
Published in print: May 2019

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Disclosure

K. O'Connor reports no disclosures; P. Waters received honoraria from Biogen, Retrogenix, Euroimmun, UBC, Mereo, holds a patent for, and receives royalties from assays for the detection of antibodies to lgi1, Caspr2, Tag-1, and GABAAR, received research support from Euroimmun, and L. Komorowski is an employee of Euroimmun; A. Zekeridou has a patent pending for PDE10A-IgG paraneplastic autoimmunity; C-Y Guo and V. Mgbachi report no disclosures. C. Probst is employed by and holds stock or stock options in Euroimmun; S. Mindorf is employed by Euroimmun; B. Teegan reports no disclosures; J.M. Gelfand served on the scientific advisory board for NIA, served on the editorial board for Neurology: Neuroimmunology & Neuroinflammation, receives royalties from Dynamed Plus, consulted for Biogen, Alexion, received research support (to University of California, San Francisco) from Genentech, MedDay, was PI of an institutional Clinician Training Award from NMSS, and received compensation for medical-legal consulting as an expert witness, and his spouse is an associate editor for JAMA, received honoraria from UpToDate, and consulted for Zosano, Eli Lilly, Biohaven, eNeura. M.D. Geschwind received speaker honoraria from Oakstone, served on the editorial board for Dementia & Neuropsychologia, and received publishing royalties from John C. Wiley, consulted for Advanced Medical, Best Doctors, Grand Rounds, Gerson Lehrman Group, Guidepoint Global, LCN Consulting Optio Biopharma, Market Plus, InThought, various Medical-legal consulting, Biohaven, Quest, received research support from Quest Diagnostics, NIH/NIA, Alliance Biosecure, Michael J. homer Family Fund, CurePSP, Tau Consortium. V.A. Lennon receives royalties from RSR/Kronus for sale of aquaporin-4 antibody testing kits and for commercial aquaporin-4 autoantibody testing performed outside Mayo Clinic and received research support from MN Partnership for Biotechnology and Medical Genomics. S.J. Pittock and Mayo Clinic have a financial interest in patents that relate to function AQP4/NMO-IgG assays and NMO as a cancer marker, and S.J. Pittock has a patent pending for GFAP, Septin-5 and MAP1B autoantibodies as biomarkers of neurologic autoimmunity, consulted for Alexion, Medimmune (paid to Mayo Clinic), and received research support from Grifols, Medimmune, Alexion, AEA, NIH. A. McKeon has patents pending for Septin 5 and MAP1B as markers of neurologic autoimmunity and paraneoplastic disorders, consulted for Grifols, Medimmune, Euroimmun, Alexion (no personal compensation), and received research support from Medimmune, Euroimmun, Grifols, Alexion. Disclosures available: Neurology.org/NN.

Study Funding

K.O'.C.'s fellowship was funded by Euroimmun, AG.

Authors

Affiliations & Disclosures

Kevin O'Connor, MD
From the Department of Laboratory Medicine and Pathology (K.O'.C., A.Z., V.L., S.J.P., A.M.), Department of Neurology (A.Z., V.L., S.J.P., A.M.), and Department of Immunology (V.L.), Mayo Clinic, Rochester, MN; Oxford Autoimmune Neurology Group (P.J.W., V.C.M.), Nuffield Department of Clinical Neurosciences, UK; Institute for Experimental Immunology (L.K., C.P., S.M., B.T.), Affiliated to Euroimmun AG, Luebeck, Germany; and the Department of Neurology (C.Y.G., J.M.G., M.D.G.), University California, San Francisco.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
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1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
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1.
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Patrick Waters, PhD
From the Department of Laboratory Medicine and Pathology (K.O'.C., A.Z., V.L., S.J.P., A.M.), Department of Neurology (A.Z., V.L., S.J.P., A.M.), and Department of Immunology (V.L.), Mayo Clinic, Rochester, MN; Oxford Autoimmune Neurology Group (P.J.W., V.C.M.), Nuffield Department of Clinical Neurosciences, UK; Institute for Experimental Immunology (L.K., C.P., S.M., B.T.), Affiliated to Euroimmun AG, Luebeck, Germany; and the Department of Neurology (C.Y.G., J.M.G., M.D.G.), University California, San Francisco.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
Honoraria from Biogen Idec, Retrogenix, Euroimmun AG, UBC and Mereo Biopharma.
Editorial Boards:
1.
NONE
Patents:
1.
Assays for the detection of antibodies to lgi1, Caspr2, Tag-1 and GABAAR.
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
Euroimmun AG
Research Support, Government Entities:
1.
NONE
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1.
NONE
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1.
NONE
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1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
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1.
Patents for CASPR2, LGI1, TAG-1 and GABAAR.
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Lars Komorowski, PhD
From the Department of Laboratory Medicine and Pathology (K.O'.C., A.Z., V.L., S.J.P., A.M.), Department of Neurology (A.Z., V.L., S.J.P., A.M.), and Department of Immunology (V.L.), Mayo Clinic, Rochester, MN; Oxford Autoimmune Neurology Group (P.J.W., V.C.M.), Nuffield Department of Clinical Neurosciences, UK; Institute for Experimental Immunology (L.K., C.P., S.M., B.T.), Affiliated to Euroimmun AG, Luebeck, Germany; and the Department of Neurology (C.Y.G., J.M.G., M.D.G.), University California, San Francisco.
Disclosure
Scientific Advisory Boards:
1.
(1) I am an employee of EUROIMMUN AG, a company that develops, produces and markets diagnostic products.
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
Employee of EUROIMMUN AG.
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
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1.
NONE
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NONE
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Anastasia Zekeridou, MD
From the Department of Laboratory Medicine and Pathology (K.O'.C., A.Z., V.L., S.J.P., A.M.), Department of Neurology (A.Z., V.L., S.J.P., A.M.), and Department of Immunology (V.L.), Mayo Clinic, Rochester, MN; Oxford Autoimmune Neurology Group (P.J.W., V.C.M.), Nuffield Department of Clinical Neurosciences, UK; Institute for Experimental Immunology (L.K., C.P., S.M., B.T.), Affiliated to Euroimmun AG, Luebeck, Germany; and the Department of Neurology (C.Y.G., J.M.G., M.D.G.), University California, San Francisco.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
Patent pending for PDE10A-IgG paraneoplastic autoimmunity
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
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1.
NONE
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1.
NONE
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Chu-Yueh Guo, MD
From the Department of Laboratory Medicine and Pathology (K.O'.C., A.Z., V.L., S.J.P., A.M.), Department of Neurology (A.Z., V.L., S.J.P., A.M.), and Department of Immunology (V.L.), Mayo Clinic, Rochester, MN; Oxford Autoimmune Neurology Group (P.J.W., V.C.M.), Nuffield Department of Clinical Neurosciences, UK; Institute for Experimental Immunology (L.K., C.P., S.M., B.T.), Affiliated to Euroimmun AG, Luebeck, Germany; and the Department of Neurology (C.Y.G., J.M.G., M.D.G.), University California, San Francisco.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
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1.
NONE
Patents:
1.
NONE
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1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
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1.
NONE
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Victor C. Mgbachi, BSc
From the Department of Laboratory Medicine and Pathology (K.O'.C., A.Z., V.L., S.J.P., A.M.), Department of Neurology (A.Z., V.L., S.J.P., A.M.), and Department of Immunology (V.L.), Mayo Clinic, Rochester, MN; Oxford Autoimmune Neurology Group (P.J.W., V.C.M.), Nuffield Department of Clinical Neurosciences, UK; Institute for Experimental Immunology (L.K., C.P., S.M., B.T.), Affiliated to Euroimmun AG, Luebeck, Germany; and the Department of Neurology (C.Y.G., J.M.G., M.D.G.), University California, San Francisco.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
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1.
NONE
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1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
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1.
NONE
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NONE
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Christian Probst, PhD
From the Department of Laboratory Medicine and Pathology (K.O'.C., A.Z., V.L., S.J.P., A.M.), Department of Neurology (A.Z., V.L., S.J.P., A.M.), and Department of Immunology (V.L.), Mayo Clinic, Rochester, MN; Oxford Autoimmune Neurology Group (P.J.W., V.C.M.), Nuffield Department of Clinical Neurosciences, UK; Institute for Experimental Immunology (L.K., C.P., S.M., B.T.), Affiliated to Euroimmun AG, Luebeck, Germany; and the Department of Neurology (C.Y.G., J.M.G., M.D.G.), University California, San Francisco.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
Euroimmun, full-time employee
Consultancies:
1.
NONE
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1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
Euroimmun
License Fee Payments, Technology or Inventions:
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Swantje Mindorf, MS
From the Department of Laboratory Medicine and Pathology (K.O'.C., A.Z., V.L., S.J.P., A.M.), Department of Neurology (A.Z., V.L., S.J.P., A.M.), and Department of Immunology (V.L.), Mayo Clinic, Rochester, MN; Oxford Autoimmune Neurology Group (P.J.W., V.C.M.), Nuffield Department of Clinical Neurosciences, UK; Institute for Experimental Immunology (L.K., C.P., S.M., B.T.), Affiliated to Euroimmun AG, Luebeck, Germany; and the Department of Neurology (C.Y.G., J.M.G., M.D.G.), University California, San Francisco.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
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1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
Employed by EUROIMMUN
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Bianca Teegen, PhD
From the Department of Laboratory Medicine and Pathology (K.O'.C., A.Z., V.L., S.J.P., A.M.), Department of Neurology (A.Z., V.L., S.J.P., A.M.), and Department of Immunology (V.L.), Mayo Clinic, Rochester, MN; Oxford Autoimmune Neurology Group (P.J.W., V.C.M.), Nuffield Department of Clinical Neurosciences, UK; Institute for Experimental Immunology (L.K., C.P., S.M., B.T.), Affiliated to Euroimmun AG, Luebeck, Germany; and the Department of Neurology (C.Y.G., J.M.G., M.D.G.), University California, San Francisco.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Jeffrey M. Gelfand, MD
From the Department of Laboratory Medicine and Pathology (K.O'.C., A.Z., V.L., S.J.P., A.M.), Department of Neurology (A.Z., V.L., S.J.P., A.M.), and Department of Immunology (V.L.), Mayo Clinic, Rochester, MN; Oxford Autoimmune Neurology Group (P.J.W., V.C.M.), Nuffield Department of Clinical Neurosciences, UK; Institute for Experimental Immunology (L.K., C.P., S.M., B.T.), Affiliated to Euroimmun AG, Luebeck, Germany; and the Department of Neurology (C.Y.G., J.M.G., M.D.G.), University California, San Francisco.
Disclosure
Scientific Advisory Boards:
1.
DSMB for a National Institutes of Aging funded study.
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
Dr. Gelfand is on the editorial advisory board of Neurology Neuroimmunology & Neuroinflammation. Dr. Gelfand's wife is an associate editor for JAMA Neurology.
Patents:
1.
NONE
Publishing Royalties:
1.
Dynamed Plus. Dr. Gelfand's spouse has received honoraria from UpToDate.
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
Dr Gelfand reports consulting for Biogen and Alexion. Dr. Gelfand's spouse has received consulting fees from Zosano Pharma Corp, Eli Lilly and Company, Biohaven Pharmaceutical and eNeura.
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
Research support (to University of California, San Francisco) from Genentech; support from a service contract from MedDay.
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
PI of an Institutional Clinician Training Award from the National MS Society.
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
Dr. Gelfand has received compensation for medical-legal consulting as an expert witness.
Michael D. Geschwind, MD, PhD
From the Department of Laboratory Medicine and Pathology (K.O'.C., A.Z., V.L., S.J.P., A.M.), Department of Neurology (A.Z., V.L., S.J.P., A.M.), and Department of Immunology (V.L.), Mayo Clinic, Rochester, MN; Oxford Autoimmune Neurology Group (P.J.W., V.C.M.), Nuffield Department of Clinical Neurosciences, UK; Institute for Experimental Immunology (L.K., C.P., S.M., B.T.), Affiliated to Euroimmun AG, Luebeck, Germany; and the Department of Neurology (C.Y.G., J.M.G., M.D.G.), University California, San Francisco.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
Speaking honoraria from Oakstone Publishing, Inc.
Editorial Boards:
1.
Editorial board, "Dementia & Neuropsychologia" ∼2010- present
Patents:
1.
NONE
Publishing Royalties:
1.
Received one time payment from John C. Wiley for 2017 publication on prion disease.
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
serves or has served as a consultant Advanced Medical Inc., Best Doctors Inc., Grand Rounds, Gerson Lehrman Group Inc, Guidepoint Global, LCN Consulting, Optio Biopharma Solutions, Market Plus, InThought Consulting various medical-legal case consulting, Biohaven Pharmaceuticals Inc., and Quest Diagnostics.
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
Quest Diagnostics, Inc.
Research Support, Government Entities:
1.
Research support from NIH/NIA R01 AG031189 PI 2013-2019, R56 AG055619-01A 2018-2019 and Alliance Biosecure 2016-18.
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
1. Michael J. Homer Family Fund 2. CurePSP 3. Tau Consortium
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Vanda Lennon, MD, PhD
From the Department of Laboratory Medicine and Pathology (K.O'.C., A.Z., V.L., S.J.P., A.M.), Department of Neurology (A.Z., V.L., S.J.P., A.M.), and Department of Immunology (V.L.), Mayo Clinic, Rochester, MN; Oxford Autoimmune Neurology Group (P.J.W., V.C.M.), Nuffield Department of Clinical Neurosciences, UK; Institute for Experimental Immunology (L.K., C.P., S.M., B.T.), Affiliated to Euroimmun AG, Luebeck, Germany; and the Department of Neurology (C.Y.G., J.M.G., M.D.G.), University California, San Francisco.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
Vanda Lennon receives royalties from RSR/Kronus for sale of aquaporin-4 autoantibody testing kits and for commercial aquaporin-4 autoantibody testing performed outside Mayo Clinic.
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
MN Partnership for Biotechnology and Medical Genomics, grant # ML2017, Chapter 89, Art, section #4 (e) Sub-award # P007067701
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
1) RSR/Kronus for sale of aquaporin-4 autoantibody testing kits. 2) Non-Mayo sites performing
Royalty Payments, Technology or Inventions:
1.
Dr. Lennon has a potential financial interest in the technologies listed below:
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Sean J. Pittock, MD
From the Department of Laboratory Medicine and Pathology (K.O'.C., A.Z., V.L., S.J.P., A.M.), Department of Neurology (A.Z., V.L., S.J.P., A.M.), and Department of Immunology (V.L.), Mayo Clinic, Rochester, MN; Oxford Autoimmune Neurology Group (P.J.W., V.C.M.), Nuffield Department of Clinical Neurosciences, UK; Institute for Experimental Immunology (L.K., C.P., S.M., B.T.), Affiliated to Euroimmun AG, Luebeck, Germany; and the Department of Neurology (C.Y.G., J.M.G., M.D.G.), University California, San Francisco.
Disclosure
Scientific Advisory Boards:
1.
Alexion Pharmaceutical Advisory Board MedImmune Advisory Board
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
Dr. Pittock and Mayo Clinic have a financial interest in patents (#12/678,350 filed 2010 and #12/573,942 filed 2008) that relate to functional AQP4/NMO-IgG assays and NMO-IgG as a cancer marker. Dr Pittock has a patent pending for GFAP, Septin-5 and MAP1B autoantibodies as biomarkers of neurological autoimmunity.
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
Dr. Pittock has provided consultation to Alexion Pharmaceuticals and Medimmune but has received no personal fees or personal compensation for these consulting activities. All compensation for consulting activities is paid directly to Mayo Clinic.
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
No activity to report. I am a salaried employee of Mayo Clinic and salary is fixed specialty dependent and not impacted by test volume or laboratory income.
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
Dr Pittock has received research funding from Grifols, Medimmune, Alexion and AEA (Autoimmune Encephalitis Associations).
Research Support, Government Entities:
1.
RO1 NS065829-01
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Andrew McKeon, MD
From the Department of Laboratory Medicine and Pathology (K.O'.C., A.Z., V.L., S.J.P., A.M.), Department of Neurology (A.Z., V.L., S.J.P., A.M.), and Department of Immunology (V.L.), Mayo Clinic, Rochester, MN; Oxford Autoimmune Neurology Group (P.J.W., V.C.M.), Nuffield Department of Clinical Neurosciences, UK; Institute for Experimental Immunology (L.K., C.P., S.M., B.T.), Affiliated to Euroimmun AG, Luebeck, Germany; and the Department of Neurology (C.Y.G., J.M.G., M.D.G.), University California, San Francisco.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
Patent applications pending: Septin 5 and MAP1B as markers of neurological autoimmunity and paraneoplastic disorders
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
Grifols Medimmune Euroimmun Alexion No personal compensation received for these activities
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
Medimmune, Inc Euroimmun Grifols Alexion
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE

Notes

Correspondence Dr. McKeon [email protected]
Funding information and disclosures are provided at the end of the article. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/NN.
The Article Processing Charge was funded by the authors.

Author Contributions

K.O'.C., P.K., L.K., V.M., C.B., B.T., S.M.: data collection, analysis, and interpretation, and critical revision of article. A.Z., C.Y.G.: data collection, analysis, and interpretation, drafting, and critical revision of article. J.M.G., M.D.G., S.J.P., V.A.L.: data collection and analysis, and critical revision of article. A.M.: study concept and design; data collection, analysis, and interpretation; drafting and critical revision of article; and study supervision.

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