Fulminant demyelinating encephalomyelitis: Insights from antibody studies and neuropathology

Abstract

Objectives: Antibodies to myelin oligodendrocyte glycoprotein (MOG) are detectable in inflammatory demyelinating CNS diseases, and MOG antibody-associated diseases seem to have a better prognosis despite occasionally severe presentations.

Methods: We report the case of a 71-year-old patient with acute visual and gait disturbance that dramatically worsened to bilateral amaurosis, tetraplegia, and respiratory insufficiency within a few days.

Results: MRI showed multiple progressive cerebral and spinal lesions with diffusion restriction (including both optic nerves) and marginal contrast enhancement. Routine blood and CSF measures including oligoclonal bands were normal. At disease onset, MOG immunoglobulin G was detected (serum titer 1:1,280, corresponding CSF titer was 1:20) and remained positive in patient serum. Aquaporin-4 antibodies were absent at disease onset but seroconverted to positive at week 9. In addition, CSF glial fibrillary acid protein and myelin basic protein levels were very high at onset but decreased during disease course. After 4 months, the patient died despite immunomodulatory treatment. Postmortem neuropathologic examination revealed an acute multiple sclerosis (MS) defined by multiple demyelinating lesions with a pronounced destructive component and loss of astrocytes. Lesion pattern of optic chiasm met MS pattern II characterized by antibody and complement-mediated demyelination.

Conclusion: The case with the clinical presentation of an acute demyelinating encephalomyelitis with predominant optic and spinal involvement, absent oligoclonal bands, a histopathology of acute MS pattern II and development of aquaporin-4 antibodies extends the spectrum of MOG antibody-associated encephalomyelitis. Although, MOG antibodies are suspected to indicate a favorable prognosis, fulminant disease courses are possible and warrant an aggressive immunotherapy.

Figure 1. Cerebral MRI during the disease course

Cerebral MRI with multiple cerebral supratentorial lesions during the disease course: periventricular lesions with diffusion restriction, only slight hyperintensity on T2-weighted images (A). Progressive diffusion restriction and now clearly hyperintense lesions on T2-weighted images 2 weeks after disease onset (B) and 4 weeks after disease onset (C). ADC = apparent diffusion coefficient.

Figure 2. Cerebral and spinal MRI

(A) Restricted diffusion of both optic nerves (arrows) on diffusion-weighted and apparent diffusion coefficient imaging. (B) Intramedullary lesions. (C) Marginal contrast enhancement at disease onset (arrows). (D) Brainstem lesions (arrows).

Figure 3. Antibody titers during the disease course

Temporal dynamic of MOG and AQP4 antibodies and time points of MRI and CSF sampling. AQP4 = aquaporin-4; MOG = myelin oligodendrocyte glycoprotein.

Figure 4. Neuropathology of MOG and AQP4 antibody–associated demyelinating lesions in the brain

The biopsy specimen revealed a small actively demyelinating lesion (A, arrow in the magnified section indicates macrophages containing LFB-positive myelin degradation products) and inflammatory infiltrates composed of CD68-positive macrophages (B), and CD8-positive T cells (C). One vessel showed perivascular deposits of activated complement complex C9neo (D, arrows). The autopsy tissue showed confluent demyelinating lesions in the brain that were immunohistochemically characterized by loss of MBP (E, rectangle enlarged in H) but contained large preoligodendrocytes that strongly labeled for CNPase (F, rectangle enlarged in I) while MOG was almost negative (G, rectangle enlarged in J; lesion borders highlighted with dotted lines). The inflammatory infiltrates mainly contained CD3-positive (K) and CD8-positive (L) T cells and perivascular CD79a-positive B cells (M). The lesion in the optic chiasm showed perivascular deposits of activated complement complex C9neo (N, arrows) and was characterized by a destructive tissue injury with loss of astrocytes in the anti-AQP4 (O), AQP1 (P), and GFAP staining (Q). One plaque in the medulla oblongata showed a selective loss of AQP4 (R; lesion border highlighted with dotted lines) while AQP1 (S) and GFAP (T) were still preserved. The astrocytes in this lesion showed clasmatodendrosis with beading or loss of processes resulting in rounded astrocytes (T, magnified sections). Magnification: E–G: ×40; A and O–T: ×100; B–D: 200×; H–N and magnified section in T: 400×; magnified section in A: 600×. AQP = aquaporin; CNPase = 2',3'-cyclic-nucleotide 3'-phosphodiesterase; GFAP = glial fibrillary acid protein; LFB = Luxol fast blue; MBP = myelin basic protein; MOG = myelin oligodendrocyte glycoprotein.