Myelin Oligodendrocyte Glycoprotein-Immunoglobulin G in the CSF: Clinical Implication of Testing and Association With Disability

Abstract

Background and objective: To investigate the clinical relevance of CSF myelin oligodendrocyte glycoprotein-immunoglobulin G (MOG-IgG) testing in a large multicenter cohort.

Methods: In this multicenter cohort study, paired serum-CSF samples from 474 patients with suspected inflammatory demyelinating disease (IDD) from 11 referral hospitals were included. After serum screening, patients were grouped into seropositive myelin oligodendrocyte glycoprotein antibody associated disease (MOGAD, 31), aquaporin-4-IgG-positive neuromyelitis optica spectrum disorder (AQP4-IgG + NMOSD, 60), other IDDs (217), multiple sclerosis (MS, 45), and non-IDDs (121). We then screened CSF for MOG-IgG and compared the clinical and serologic characteristics of patients uniquely positive for MOG-IgG in the CSF to seropositive patients with MOGAD.

Results: Nineteen patients with seropositive MOGAD (61.3%), 9 with other IDDs (CSF MOG + IDD, 4.1%), 4 with MS (8.9%), but none with AQP4-IgG + NMOSD nor with non-IDDs tested positive in the CSF for MOG-IgG. The clinical, pathologic, and prognostic features of patients uniquely positive for CSF MOG-IgG, with a non-MS phenotype, were comparable with those of seropositive MOGAD. Intrathecal MOG-IgG synthesis, observed from the onset of disease, was shown in 12 patients: 4 of 28 who were seropositive and 8 who were uniquely CSF positive, all of whom had involvement of either brain or spinal cord. Both CSF MOG-IgG titer and corrected CSF/serum MOG-IgG index, but not serum MOG-IgG titer, were associated with disability, CSF pleocytosis, and level of CSF proteins.

Discussion: CSF MOG-IgG is found in IDD other than MS and also in MS. In IDD other than MS, the CSF MOG-IgG positivity can support the diagnosis of MOGAD. The synthesis of MOG-IgG in the CNS of patients with MOGAD can be detected from the onset of the disease and is associated with the severity of the disease.

Classification of evidence: This study provides Class II evidence that the presence of CSF MOG-IgG can improve the diagnosis of MOGAD in the absence of an MS phenotype, and intrathecal synthesis of MOG-IgG was associated with increased disability.

Figure 1. Diagnostic Flow and CSF MOG-IgG Assay Results

(A) The flowchart of study participants. (B) Examples of CSF assay for MOG-IgG. (C) The MFI ratio of CSF MOG-IgG assays in all participants. Among 474 patients, 19 seropositive MOGAD, 9 other IDDs, and 4 patients with MS were positive for CSF MOG-IgG. None with AQP4-IgG + NMOSD or with non-IDDs had positive results for CSF MOG-IgG. Red dots indicate samples obtained at the time of first attack, and black dots indicate those at relapsing attacks. The MFIr are plotted in logarithmic axis. AQP4-IgG + NMOSD = aquaporin-4 immunoglobulin G positive neuromyelitis optica spectrum disorder; AQP4+ = aquaporin-4 antibody positive; CIS = clinically isolated syndrome; IDD = inflammatory demyelinating disease; IgG = immunoglobulin G; MFIr = mean fluorescence intensity ratio; MOG = myelin oligodendrocyte glycoprotein; MOGAD = myelin oligodendrocyte glycoprotein antibody associated disease; MS = multiple sclerosis.

Figure 2. Radiologic Findings of CSF MOG + Patients With IDD

(A) Case 1: The brain MRI shows T2 HSI lesions at the right basal ganglia and external capsules in patients who presented with seizure. (B) Case 3: Multiple T2 HSI lesions in the cortex and deep gray matters in the brain MRI of a patient with headache and tetraparesis. (C) After treatment with interferon beta for 5 months, the patient relapsed with multiple cortical and deep gray matter lesions. Her treatment was switched to rituximab, and she had been relapse-free for 3.3 years (D) Case 5: Large, confluent, and disseminated cortical-subcortical lesions and a lesion in the left cerebral peduncle in the brain MRI of a patient who presented with headache, dysarthria, and cognitive Impairment. (E) Her symptoms improved after combined treatment with steroids, intravenous immunoglobulin, and plasmapheresis, and oral steroid maintenance was administered for 5 months 10 days after the cessation of oral steroid treatment. The patient experienced left facial palsy, and her MRI revealed a new lesion involving the right thalamus and internal capsule. She began treatment with rituximab and had been relapse-free for 7 years (F) An MRI taken 7 years after disease onset reveals severe brain atrophy that is more severe in the areas involved in previous attacks. (G) Case 6: Multiple lesions in the pons, unilateral cortex (arrow head), subcortex, medulla, and spinal cord in a patient with visual disturbance, dysarthria, dysphagia, and quadriparesis. (H) Case 2; Lesions involving the unilateral cerebral cortex (arrow head), right thalamus, and cerebral peduncle in a patient with seizures. (I) Case 8: Left optic nerve lesion with asymptomatic cervical spinal cord lesion (arrow head) in a patient with left optic neuritis. (J) Case 9: Right optic nerve lesion with asymptomatic parietal subcortical lesion (arrow head) in a patient with right optic neuritis. HSI = high signal intensity; MOGAD = myelin oligodendrocyte glycoprotein antibody associated disease.

Figure 3. Histopathologic Findings of 2 CSF MOG + IDD (Cases 1 and 5)

Case 1: (A) The lesion shows marked macrophage infiltration and focal mild perivascular lymphocytic infiltration with reactive astrocytes (arrows). There are some Creutzfeldt-Jakob cells (inlet). (B) Markedly demyelinated lesions with myelin fragment-laden macrophages (LFB) are observed, but (C) axons are relatively preserved (NF). (D) CD4-positive T-cells and (E) CD8-positive T-cells are found in perivascular area. (F) AQP4 immunostain is positive in the membrane of reactive astrocytes, whereas (G) loss of MOG staining is observed in the demyelinated area. (H) Activated complement components (C9neo) are negative for infiltrating macrophages (most negative cells in this figure), but positive in the reactive astrocytes (arrows). Case 5: (I) The lesion also shows marked macrophage infiltration and focal perivascular lymphocytic infiltration. (J) Marked demyelination with myelin fragment-laden macrophages (LFB) but (K) relatively preserved axons (NF) are shown. (L) CD4-positive T-cells are numerous in the perivascular area and scattered in the brain parenchyma, but (M) CD8-positive T-cells are rare. (N) AQP4 is preserved in the membrane of reactive astrocytes, but (O) loss of MOG is predominant. (P) In the infiltrating macrophages and reactive astrocytes (arrows), activated complement components are observed (C9neo). AQP4 = aquaporin-4; CD = cluster of differentiation; H&E = hematoxylin and eosin; LFB = Luxol fast blue; MOG = myelin oligodendrocyte glycoprotein; MOGAD = myelin oligodendrocyte glycoprotein antibody associated disease; NF = neurofilament.

Figure 4. Corrected CSF/Serum MOG-IgG Index, Lesion Location, and Clinical Diagnosis in the MOGAD Group

MOG-IgG titers were measured in both the serum and CSF of 36 patients with MOGAD (28 seropositive MOGAD and 8 CSF MOG + IDD) with a sufficient volume of samples, and the corrected CSF/serum MOG-IgG index was calculated. (A) The corrected CSF/serum MOG-IgG index according to the MOG-IgG titer in the serum and the CSF. Twelve patients with MOGAD (4 seropositive and 8 CSF positive only) have a corrected CSF/serum MOG-IgG index exceeding 4 or MOG-IgG in CSF only and are thereby determined to have intrathecal MOG-IgG synthesis. The CSF/serum MOG-IgG indices could not be calculated because 3 patients were negative for serum MOG-IgG (red box). (B–C) Patients with brain/spinal cord lesions or only optic nerve involvement are significantly different in (B) MOG-IgG positivity in the serum and/or CSF, and (C) intrathecal MOG-IgG synthesis. (D) Clinical diagnoses of patients with MOGAD based on intrathecal MOG-IgG synthesis. All patients with intrathecal MOG-IgG synthesis (+) had involvement in the brain/spinal cord; most (58.3%) manifested with a clinical diagnosis of ADEM. In contrast, in the intrathecal MOG-IgG synthesis (−) group, iON was the most common (75.0%) diagnosis. ADEM = acute disseminated encephalomyelitis; CIS = clinically isolated syndrome; iATM = idiopathic acute transverse myelitis; iON = idiopathic optic neuritis; MOG-IgG = myelin oligodendrocyte glycoprotein immunoglobulin G; MOGAD = myelin oligodendrocyte glycoprotein antibody associated disease; NMOSD = neuromyelitis optica spectrum disorder; SC = spinal cord.

Figure 5. Correlation Between MOG-IgG Titers and Clinical Severity

The MOG-IgG titer and its correlation with the degree of disability, number of white blood cells in the CSF, and level of protein in patients with MOGAD are associated with the MOG-IgG titer (A) in the CSF, but (B) not in the serum. (C) They are also associated with the corrected CSF/serum MOG-IgG index. EDSS = Kurtzke expanded disability status scale; MOG-IgG = myelin oligodendrocyte glycoprotein immunoglobulin G; MOGAD = myelin oligodendrocyte glycoprotein antibody associated disease; WBC = white blood cell.