Background
Methods
Recommendations on MOG-IgG testing
1. Monophasic or relapsing acute optic neuritis, myelitis, brainstem encephalitis, encephalitis, or any combination thereof,
and
2. radiological or, only in patients with a history of optic neuritis, electrophysiological (VEP) findings compatible with CNS demyelination,
and
3. at least one of the following findings:
MRI
a. Longitudinally extensive spinal cord lesion (≥3 VS, contiguous) on MRI (so-called LETM)a,b b. Longitudinally extensive spinal cord atrophy (≥3 VS, contiguous) on MRI in patients with a history compatible with acute myelitisa c. Conus medullaris lesions, especially if present at onsetc d. Longitudinally extensive optic nerve lesion (e.g., >1/2 of the length of the pre-chiasmal optic nerve, T2 or T1/Gd)d e. Perioptic Gd enhancement during acute ONe f. Normal supratentorial MRI in patients with acute ON, myelitis and/or brainstem encephalitis g. Brain MRI abnormal but no lesion adjacent to a lateral ventricle that is ovoid/round or associated with an inferior temporal lobe lesion and no Dawson’s finger-type or juxtacortical U fiber lesion (Matthews-Jurynczyk criteriaf) h. Large, confluent T2 brain lesions suggestive of ADEM
Fundoscopy
i. Prominent papilledema/papillitis/optic disc swelling during acute ON
CSF
j. Neutrophilic CSF pleocytosisg or CSF WCC > 50/μlh k. No CSF-restricted OCB as detected by IEF at first or any follow-up examinationi (applies to continental European patients only)
Histopathology
l. Primary demyelination with intralesional complement and IgG deposits m. Previous diagnosis of “pattern II MS” j
Clinical findings
n. Simultaneous bilateral acute ON o. Unusually high ON frequency or disease mainly characterized by recurrent ON p. Particularly severe visual deficit/blindness in one or both eyes during or after acute ON q. Particularly severe or frequent episodes of acute myelitis or brainstem encephalitis r. Permanent sphincter and/or erectile disorder after myelitis s. Patients diagnosed with “ADEM”, “recurrent ADEM”, “multiphasic ADEM” or “ADEM-ON” t. Acute respiratory insufficiency, disturbance of consciousness, behavioral changes, or epileptic seizures (radiological signs of demyelination required) u. Disease started within 4 days to ~ 4 weeks after vaccination v. Otherwise unexplained intractable nausea and vomiting or intractable hiccups (compatible with area postrema syndrome)a w. Co-existing teratoma or NMDAR encephalitis (low evidencek)
Treatment response
x. Frequent flare-ups after IVMP, or steroid-dependent symptomsl (including CRION) y. Clear increase in relapse rate following treatment with IFN-beta or natalizumab in patients diagnosed with MS (low evidence) |
Example 1: 35-year-old woman presenting with bilateral acute ON. Develops transient blindness; fundoscopy shows papilledema; lumbar puncture reveals lymphomonocytic pleocytosis with 10% neutrophils and negative OCBs; brain MRI shows perioptic Gd enhancement but is otherwise normal; flaring up of symptoms after tapering of oral steroids; later recurrent ON attacks, stabilization with rituximab. Example 2: 40-year-old woman with two attacks of acute, OCB-negative myelitis. Spine MRI shows an isolated short spinal cord lesion at first attack and a longitudinally extensive spinal cord lesion at relapse; brain MRI abnormal but no Dawson’s finger-type lesion, no juxtacortical U fibre lesion, and no lesion adjacent to a lateral ventricle that is ovoid or associated with an inferior temporal lobe lesion [36, 37, 50]; flaring up of myelitis symptoms after discontinuation of intravenous steroid treatment, good response to PEX. Example 3: Young man with a previous diagnosis of “OCB-negative RRMS”. Predominantly ON and myelitis attacks; conus lesion with severe erectile and sphincter disturbance after first myelitis; longitudinally extensive optic nerve lesion with involvement of the optic chiasm; increase in relapse rate under treatment with interferon-beta but stabilization with rituximab. Example 4: 42-year-old woman presenting with incomplete, painful tetraparesis. Previous diagnosis of RRMS with positive OCB; spinal cord MRI reveals a contiguous lesion extending from C3 to T1; negative serology for AQP4-IgG. Example 5: ADEM-like presentation with large white matter lesions and disturbance of consciousness, brainstem lesions, and involvement of the entire spinal cord in a 25-year-old woman; onset 3 weeks after vaccination. Example 6: Simultaneous unilateral ON and LETM extending into the brainstem in a 39-year-old man. CSF pleocytosis (90 white cells/μl) with 5% neutrophils; no CSF-restricted OCB; negative AQP4-IgG serostatus. Example 7: Young woman presenting with recurrent and steroid-dependent isolated ON, previously classified as CRION; normal brain MRI. Example 8: Young man with acute encephalitis and seizures. MRI reveals large cortical/subcortical white matter lesions not involving the inferior temporal lobe; good response to steroids; negative for typical viral and autoimmune causes of encephalitis. |
Assay types Cell-based assays (IFT/FACS): Recommended (current gold standard); must employ full-length human MOG as target antigen; use of Fc-specific (or IgG1-specific [63]) secondary antibodies highly recommended to avoid cross-reactivity with (specifically or non-specifically co-binding) IgM and IgA antibodies [11, 63] Immunohistochemistry: Currently not recommended (less sensitive than cell-based assays, limited data available on specificity [11, 64], sensitivity depends on tissue donor species [64]); if used, Fc-specific secondary antibodies adsorbed against tissue donor IgG required in order to avoid cross-reactivity with IgM and IgA or with tissue-bound donor IgG Peptide-based ELISA, Western blot: Insufficiently specific, obsolete Biomaterial Serum: Recommended (specimen of choice); shipment at 4 °C or on dry ice advisable if samples do no arrive within 1–2 days Cerebrospinal fluid: Not usually required, since MOG-IgG is produced mostly extrathecally, resulting in lower CSF than serum titers [2]; potentially helpful in rare, selected cases (e.g., strong background due to co-existing high-titer non-MOG serum antibodies); shipment at 4 °C or on dry ice advisable Immunoglobulin classes Testing for MOG-IgG: Recommended Testing for MOG-IgM and/or MOG-IgA: Currently not recommended; additional MOG-IgM and MOG-IgA antibodies have been described in some MOG-IgG-positive patients [1, 2]; the clinical relevance of isolated MOG-IgM or -IgA results is unknown; testing for antibodies of the IgM class requires removal of total IgG from the sample to avoid both false-negative (due to high-affinity IgG displacing IgM) and false-positive (due to IgM anti-IgGFc rheumatoid factors) results [65] Data reporting Immunoglobulin class detected, assay type, antigenic substrate and biomaterial used, titer/concentration/units, assay-specific cut-offs and performing laboratory should all be documented (e.g., “Serum MOG-IgG 1:1280 [cut-off ≥ 1:160a; assay: live CBA, Innsbruck lab; antigen: full-length human MOG]”) Data interpretation As with all laboratory tests, positive test results should always be interpreted in the context of the patient’s overall presentation; if “red flags” as defined in Table 4 are present, re-testing of the positive serum sample (or, if not anymore available, at least testing of a follow-up serum sample) is recommended; to reduce the potential risk of reproducing false-positive results due to issues inherent to the very method employed, use of a second (and, in the case of discrepant results, third) methodologically different cell-based assay is advisable; if in doubt, seek expert advice from a specialized center Timing issues MOG-IgG serum concentrations depend on disease activity (with higher median concentrations during acute attacks than during remission) and treatment status (with lower concentrations while on immunosuppression) and may transiently vanish after plasma exchange [3]; if MOG-IgG is negative but MOG-EM still suspected, re-testing during acute attacks, during treatment-free intervals, or 1–3 months after plasma exchange (or IVIGb) is recommended – N.B.: Some cases of monophasic MOG-positive EM/ADEM in adult patients have been described in which MOG-IgG disappeared permanently following clinical recovery [2‐4, 33‐35] |
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.)
MRI
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)
CSF
Bi- or trispecific MRZ reactionb (consider MS)
Serology
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
Others
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 |