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Table 4 “Red flags”: conditions that should prompt physicians to challenge a positive test result (consider re-testing the patient, ideally using an alternative, i.e., methodologically different cell-based assay; in case of doubt, consider seeking expert advice from a specialized center)

From: MOG encephalomyelitis: international recommendations on diagnosis and antibody testing

Disease course
 Chronic progressive disease (very rare in MOG-IgG-positive patients [3]), including SPMS (especially SPMS without relapses) and PPMSa
 Sudden onset of symptoms, e.g., < 4 h from onset to maximum (consider ischemic cause), or continuous worsening of symptoms over weeks (consider tumor, sarcoidosis, etc.)
 Lesion adjacent to a lateral ventricle that is ovoid/round or associated with an inferior temporal lobe lesion, or Dawson’s finger-type lesion
 Active brain MRI over time with silent increase in lesion burden between relapses (limited evidence)
 Bi- or trispecific MRZ reactionb (consider MS)
 MOG-IgG levels at or just barely above the assay-specific cut-offc, especially (but not exclusively) if clinical picture is atypical
 Positive MOG-IgM and/or MOG-IgA result with negative MOG-IgG (clinical significance unknown)
 MOG-IgG positivity in the CSF but not in the serumd (MOG-IgG is typically produced extrathecally)
 AQP4-IgG/MOG-IgG “double-positive” test results (extremely rare; should prompt retesting for both antibodies)e
 Clinical or paraclinical findings suggesting diagnoses other than MOG-EM, NMOSD or MS (e.g., neurotuberculosis, neuroborreliosis, neurosyphilis, neurosarcoidosis, Behçet syndrome, subacute combined degeneration of the spinal cord, Leber’s hereditary optic neuropathy, vasculitis, CNS lymphoma, gliomatosis cerebri, paraneoplastic neurological disordersf, PRES, PML, and evidence for CNS infectiong)
 Combined central and peripheral demyelination [69] (MOG is not expressed in the peripheral nervous system)h
  1. Abbreviations: AQP4 aquaporin-4, CNS central nervous system, CSF cerebrospinal fluid, EM encephalomyelitis, Ig immunoglobulin, MOG myelin oligodendrocyte glycoprotein, MRZ measles, rubella and zoster virus, MS multiple sclerosis, NMDAR N-methyl-D-aspartate receptor, NMOSD neuromyelitis optica spectrum disorder, PPMS primary progressive MS, PML progressive multifocal leukoencephalopathy, PRES posterior reversible encephalopathy syndrome, SPMS secondary progressive MS, WCC white cell count
  2. aJust one borderline MOG-IgG result found among 290 patients with PPMS (n = 174) or SPMS (n = 116) in a recent study [29]
  3. bMeasles (M), rubella (R), and zoster (Z) reaction: Intrathecal synthesis against at least two of these three viral agents (i.e., against M + R, M + Z, R + Z, or M + R + Z); part of the polyspecific, intrathecal humoral immune reaction in MS; present in around 70% of MS patients but not at all, or only very rarely, in MOG- or AQP4-IgG-positive patients (MOG-EM: 0/11; NMO: 1/42; “ADEM”: 1/26) [3, 70, 71]
  4. cExcept in patients who were previously positive at levels clearly above the cut-off, in which case low-titer results may reflect true (spontaneous or treatment-related) decline in antibody levels
  5. dMay be valid in the rare instances in which co-existing serum autoantibodies hamper serum analysis but not CSF analysis (false-negative serum test)
  6. eIf confirmed in a second assay and IPND criteria for NMOSD are met, co-existence of MOG-EM and AQP4-NMOSD must be assumed
  7. fNote, however, that preliminary reports suggest occasional co-incidence of MOG-EM and NMDAR encephalitis [61]; in such patients teratoma needs to be excluded [60]
  8. gNote that CSF findings in MOG-EM (as well as in AQP4-NMOSD) may mimic CNS infection with neutrophil pleocytosis, impaired blood-CSF barrier function, and a lack of CSF-restricted oligoclonal bands [3, 40, 51]. White cell counts in MOG-EM ranged between 6 and 306 cells/μl (median 33; quartile range 13–125) in a recent European study [2]; WCC ≥ 100 cells/μl were present at least once in 9/32 (28.1%) patients; neutrophil granulocytes were present at least once in 9/14 (64.3%) patients with pleocytosis and available data (median 22% of all white cells; range 3–69%)
  9. hMay be true positive in the rare cases in which MOG-EM and unrelated peripheral neuropathy of other cause co-exist