Peripherally derived macrophages as major phagocytes in MOG encephalomyelitis

Case report

A 34-year-old male patient presented with sudden disorientation in September 2018. The neurologic examination showed disturbed consciousness with a Mini-Mental State Examination score of 17. Brain MRI showed multiple enhancing and T2 high signal intensity (HSI) lesions in both periventricular and deep white matter of the cerebrum, cerebellum, and upper medulla oblongata (figure, A). A CSF analysis demonstrated a cell count of 20 cells/μL (18 lymphocytes) and a slightly elevated protein level (50 mg/dL). The oligoclonal bands were positive, and IgG index was 0.61. Whole-body 18F-fluorodeoxyglucose PET revealed multifocal white matter lesions with mild hypermetabolism suggesting active inflammation rather than the malignancy. Initial EEG showed no epileptiform discharge. Serum fluorescent antinuclear antibody, antineutrophil cytoplasmic antibody, human T-cell lymphotropic virus antibody, cryoglobulin, anticardiolipin antibody, anti-β₂-glycoprotein 1 antibody, and aquaporin-4 antibody were all negative. CSF cytology test showed no evidence of malignant cell. We suspected acute disseminated encephalomyelitis (ADEM) at first, and high-dose IV methylprednisolone (IVMP, 1 g for 5 days) following oral prednisolone (60 mg/d) were administered. As the follow-up brain MRI revealed improvement in T2 HSI lesion volume, we gradually tapered out prednisolone over 1 month.

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Figure Brain MRI, neuropathology, and MOG-IgG assay results of the patient

(A) His initial brain MRI showed multiple enhancing and T2 HSI lesions in both periventricular and deep white matter of the cerebrum, cerebellum, and upper medulla oblongata at first attack. The right parietal white matter was almost preserved at first attack (yellow circles). (B) Follow-up brain MRI, taken 2 months after first attack, revealed diffuse contiguous spinal T2 HSI lesion in T3–T5 spinal cord and increased number and extent of multiple T2 in his brain. Stereotactic brain biopsy was performed at gadolinium-enhancing lesion at the right parietal lobe (yellow circles). (C) The lesion is heavily infiltrated by foamy phagocytic cells with perivascular lymphocytic infiltration and reactive gliosis (arrows) (H&E stain). (D and E) Luxol fast blue and myelin basic protein stains show nearly complete demyelination. (F and G) The demyelinating area is heavily infiltrated by CD68⁺ and CD163⁺ foamy macrophages (Gitter cells), (H) but only few of them were positive for TMEM119. (I and J) The CD3 and CD8 delineate parenchymal T-cell and cytotoxic T-cell infiltration in the brain parenchyma and perivascular area. (K) However, the CD20 demonstrates perivascular B-cell infiltration. (L and M) The MOG-IgG assay result in healthy control and this patient. (N) TMEM119 staining in a positive control; brain tissue from a patient with glioblastoma; Magnification bars: 200 μm. LFB = luxol fast blue; MBP = myelin basic protein; MOG = myelin oligodendrocyte glycoprotein; TMEM119 = transmembrane protein 119.

Two weeks after discontinuation of prednisolone (2 months after first attack), he developed the patient returned with acute confusion and a bilateral tingling sensation below the T6 sensory dermatome level. Spinal cord imaging showed a diffuse contiguous T2 HSI lesion in T3 to T5. Brain MRI revealed increasing multiple T2 HSI and enhanced lesions on the right temporoparietal white matter, right occipital lobe, and both high frontoparietal lobes suggesting aggravated state of demyelinating disease or malignancy (figure, B). Because of diagnostic uncertainty, a stereotactic brain biopsy was performed in gadolinium-enhancing lesion of the right parietal lobe in early November 2018. He was treated again with IVMP. Serum MOG-IgG1 antibodies were detected by flow cytometry as described previously (figure, L and M).⁷

The neuropathology revealed severe demyelination with diffuse infiltration of the foamy CD68⁺ phagocytic cells, focal mild perivascular lymphocytic infiltration, reactive astrogliosis, and a few Creutzfeldt cells. CD68⁺ cells were abundant in diffuse parenchymal lesion, but all of them were negative for TMEM119. Many of CD3⁺ or CD8⁺ T cells were observed in the brain parenchyma and perivascular area, whereas CD20⁺ B cells were observed only in the perivascular area (figure, C–K, and N). Brain tissue from a patient with glioblastoma was used as a positive control for TMEM119 staining, which revealed abundant TMEM119-positive cells.