The 2015 international consensus diagnostic criteria for neuromyelitis optica spectrum disorder (NMOSD) was created to identify adult patients with similar clinical and radiological phenotypes, distinct from multiple sclerosis.1 It includes patients who are seropositive for aquaporin-4 immunoglobulin G (AQP4-IgG) and those who are seronegative. These criteria were created prior to the current understanding of myelin oligodendrocyte glycoprotein–IgG (MOG-IgG1)–associated disorders (MOGAD). Although MOGAD has some phenotypic overlap with AQP4-IgG and NMOSD, there are many clinical, radiologic, serologic, and prognostic differences.2-6 There is inconsistent use of diagnostic MOG-IgG1 terminology for MOGAD, with many neurologists using the term seronegative NMOSD. We sought to evaluate the proportion of patients with MOGAD who fulfill the seronegative NMOSD criteria.1
This is a retrospective study approved by the institutional review board of Mayo Clinic (08-00647) using clinical and radiological data from Mayo Clinic patients with MOGAD (MOG-IgG1+ by flow cytometric assay) who provided written consent for research. The 2015 NMOSD diagnostic criteria were applied.1 Descriptive statistics included Fisher exact and Wilcoxon rank sum tests (2-sided P value <.05 was considered statistically significant).
Demographic and clinical characteristics are shown in the Table. Among adults, 26 (23%) met seronegative NMOSD criteria (median time, 7.1 months; interquartile range [IQR], 2.3-23.3). Core clinical characteristics included optic neuritis (ON) and longitudinally extensive transverse myelitis (LETM) (n = 20 [77%]), ON and diencephalon lesions with diencephalon attack in the context of acute disseminated encephalomyelitis (ADEM) (n = 4 [15%]), and LETM and brainstem syndrome with brainstem periependymal lesions (n = 2 [8%]) (Figure).
Among children, 17 (31%) met the seronegative NMOSD criteria (median time of 12.1 months; IQR, 2.2-64.7 months). Core clinical characteristics included ON and LETM (n = 10 [59%]), ON and diencephalon lesions with diencephalon attack in the context of ADEM (n = 5 [29%]), LETM and brainstem syndrome with brainstem peri-ependymal lesion (n = 1 [6%]), and LETM with diencephalon attack in the context of ADEM (n = 1 [6%]) (Table).
In the subgroup of patients who had a relapsing course (64 adults and 39 children), 24 adults (38%) and 16 children (41%) met the seronegative NMOSD criteria (Table). In the subgroup of patients with more than 2 years of follow-up from disease onset (52 adults and 10 children), 16 adults (31%) and 12 children (30%) met seronegative NMOSD criteria (Table).
Among patients with MOGAD, 23% of adults and 31% of children fulfilled the seronegative NMOSD criteria. The proportion of cases meeting the seronegative NMOSD criteria increased slightly when subgroups restricted to more than 2-year follow-up or a relapsing course were analyzed.
The most common attacks in our MOGAD cohort were ON and myelitis. However, most had isolated ON (monophasic or recurrent) or isolated myelitis. Further, more than one-third of patients with MOGAD myelitis (38%) did not have LETM. Therefore, only 29 patients with MOGAD fulfilled the NMOSD criteria using the clinical and radiological criteria for ON and LETM. Optic neuritis not extending more than one-half of the optic nerve nor involving the chiasm and associated with large cerebral ADEM lesions does not meet the optic neuritis criteria due to the requirement of a normal brain magnetic resonance imaging (MRI) (Figure).1
Although nausea and vomiting can occur in MOGAD, the defined core clinical characteristic of area postrema syndrome (more than 48 hours of intractable nausea, vomiting, or hiccups) without a secondary cause and a discrete, isolated MRI lesion in the area postrema/dorsal medulla is rarely encountered.2 Brainstem lesions are common but do not necessarily correspond to a brainstem clinical attack and occur as part of multifocal demyelination in ADEM. Brainstem lesions are often diffuse and are not necessarily discrete periependymal lesions, as defined in the seronegative criteria (Figure).1
The limitations of this study include referral bias to Mayo Clinic for patients with severe and relapsing MOGAD, which may overestimate the number of patients who fulfill the seronegative NMOSD criteria. This study demonstrates that 2015 diagnostic criteria for seronegative NMOSD fail to capture most patients who have MOGAD and supports specific molecular biomarker-associated diagnostic criteria for inflammatory central nervous system disorders.
Corresponding Author: Sean J. Pittock, MD, Department of Neurology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (firstname.lastname@example.org).
Published Online: August 10, 2020. doi:10.1001/jamaneurol.2020.2743
Accepted for Publication: June 3, 2020.
Conflict of Interest Disclosures: Dr Wingerchuk has received research funding from Alexion and TerumoBCT; personal compensation consulting for MedImmune, Novartis, Biogen, Celgene, Genentech, TG Therapeutics, Arcus Medica, Third Rock Ventures, and Reistone; and served on an adjudication committee for a neuromyelitis optica (NMO) clinical trial sponsored by MedImmune and Viela Bio. Dr Weinshenker receives royalties from RSR Ltd, Oxford University, Hospices Civil de Lyon, and MVZ Labor PD Dr Volkmann und Kollegen GbR for a patent of NMO-IgG as a diagnostic test for NMO and related disorders; served on adjudication committee for clinical trials in NMO conducted by MedImmune and Alexion; and consulted for Chugai and Mitsubishi Tanabe regarding clinical trials for NMO. Dr Flanagan is a site principal investigator in a randomized placebo-controlled clinical trial of inebilizumab (a CD19 inhibitor) in neuromyelitis optica spectrum disorders funded by MedImmune/Viela Bio. Dr Pittock reports grants, personal fees and nonfinancial support from Alexion Pharmaceuticals, Inc; grants from Grifols and Autoimmune Encephalitis Alliance; grants, personal fees, nonfinancial support, and other support from MedImmune Inc; Dr Pittock also has a patent (application 12-573942) “Methods for Treating Neuromyelitis Optica (NMO) by Administration of Eculizumab to an individual that is Aquaporin-4 (AQP4)-IgG Autoantibody positive.” Dr Pittock also has patents pending for the following IgGs as biomarkers of autoimmune neurological disorders: septin-5, Kelch-like protein 11, GFAP, PDE10A and MAP1B.
Funding/Support: National Institutes of Health National Institute of Neurological Disorders and Stroke (grant R01NS113828).
Role of the Funder/Sponsor: The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Additional Contributions: We thank Mary Curtis for her administrative support, Solmaz Asnafi, MD, Emory University, Atlanta, Georgia, for assistance with early data collection, and Andrew McKeon, MD, Mayo Clinic, Rochester, Minnesota, for his review of an earlier draft.
et al. The pathology of central nervous system inflammatory demyelinating disease accompanying myelin oligodendrocyte glycoprotein autoantibody. Acta Neuropathol
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