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. 2014 Oct 29;1(4):e40.
doi: 10.1212/NXI.0000000000000040. eCollection 2014 Dec.

Antibodies to myelin oligodendrocyte glycoprotein in bilateral and recurrent optic neuritis

Sudarshini Ramanathan  1 , Stephen W Reddel  1 , Andrew Henderson  1 , John D E Parratt  1 , Michael Barnett  1 , Prudence N Gatt  1 , Vera Merheb  1 , Raani-Yogeeta Anusuiya Kumaran  1 , Karrnan Pathmanandavel  1 , Nese Sinmaz  1 , Mahtab Ghadiri  1 , Con Yiannikas  1 , Steve Vucic  1 , Graeme Stewart  1 , Andrew F Bleasel  1 , David Booth  1 , Victor S C Fung  1 , Russell C Dale  1 , Fabienne Brilot  1
Affiliations

Antibodies to myelin oligodendrocyte glycoprotein in bilateral and recurrent optic neuritis

Sudarshini Ramanathan et al. Neurol Neuroimmunol Neuroinflamm. .

Abstract

Objective: We examined a cohort of adults with aquaporin-4 (AQP4) antibody-negative neuromyelitis optica/neuromyelitis optica spectrum disorder (NMO/NMOSD) for antibodies to myelin oligodendrocyte glycoprotein (MOG).

Methods: We performed a flow cytometry cell-based assay using live human lentivirus-transduced cells expressing full-length surface MOG. Serum was tested in 23 AQP4 antibody-negative NMO/NMOSD patients with bilateral and/or recurrent optic neuritis (BON, n = 11), longitudinally extensive transverse myelitis (LETM, n = 10), and sequential BON and LETM (n = 2), as well as in patients with multiple sclerosis (MS, n = 76) and controls (n = 52).

Results: MOG antibodies were detected in 9/23 AQP4 antibody-negative patients with NMO/NMOSD, compared to 1/76 patients with MS and 0/52 controls (p < 0.001). MOG antibodies were detected in 8/11 patients with BON, 0/10 patients with LETM, and 1/2 patients with sequential BON and LETM. Six of 9 MOG antibody-positive patients had a relapsing course. MOG antibody-positive patients had prominent optic disc swelling and were more likely to have a rapid response to steroid therapy and relapse on steroid cessation than MOG antibody-negative patients (p = 0.034 and p = 0.029, respectively). While 8/9 MOG antibody-positive patients had good follow-up visual acuity, one experienced sustained visual impairment, 3 had retinal nerve fiber layer thinning, and one had residual spinal disability.

Conclusions: MOG antibodies have a strong association with BON and may be a useful clinical biomarker. MOG antibody-associated BON is a relapsing disorder that is frequently steroid responsive and often steroid dependent. Failure to recognize the disorder early and institute immunotherapy promptly may be associated with sustained impairment.

Classification of evidence: This study provides Class II evidence that MOG antibodies are associated with AQP4 antibody-negative BON (sensitivity 69%, 95% confidence interval [CI] 42%-87%; specificity 99%, 95% CI 93.7%-99.8%).

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Figures

Figure 1
Figure 1. MOG antibodies are associated with BON in adults
(A) Antibody (Ab) reactivity to myelin oligodendrocyte glycoprotein (MOG) was determined by a flow cytometry live cell-based assay and demonstrated increased immunoglobulin (Ig) G binding to MOG with an increasing MOG antibody concentration. (B, C) Representative examples of flow cytometry histograms for one MOG antibody–positive patient with an intermediate ΔMFI (B) and one with a very high ΔMFI (C). ΔMFI values are noted in the legend. (D) Human surface MOG IgG Abs were detected in 9/23 AQP4 antibody–negative patients with NMO/NMOSD, compared to 1/76 patients with multiple sclerosis (MS) and 0/52 controls. The red line on the graph represents the threshold of positivity. MOG antibody positivity is shown between brackets. A representative experiment out of 3 is shown. (E) ΔMFI values for all subgroups of AQP4 antibody–negative patients with NMO/NMOSD. AQP4 = aquaporin-4; BON = bilateral and/or recurrent optic neuritis; HEK293 = human embryonic kidney 293 cells; HEK293CTL = control HEK293 cells; HEK293MOG+ = HEK293 cells expressing MOG; LETM = longitudinally extensive transverse myelitis; MFI = mean fluorescence intensity; NMO/NMOSD = neuromyelitis optica /neuromyelitis optica spectrum disorder.
Figure 2
Figure 2. MOG antibody seropositivity in patients with MOG antibody–associated BON
(A) Serial dilutions of MOG antibody–positive samples show differing immunoglobulin (Ig) G binding. The end point dilution where a sample remained above the positive threshold (red line) ranged from 1:50 to 1:2,000. For clarity, only 3 representative patients are shown. (B–E) Serial samples in 4 MOG antibody–positive patients are shown. A representative dot plot out of 3 experiments is shown. Red lines on the graphs represent the threshold of positivity. Black circles represent times of serum collection, arrows pointing up represent a clinical attack, arrows pointing down represent commencement of treatment. (B) Patient 1 experienced a unilateral episode of left optic neuritis (ON) (normal MRI brain) that responded rapidly to pulsed steroids; however, cessation of steroids prompted a bilateral simultaneous ON relapse requiring further treatment. There were no further relapses and a good visual outcome. The initial sample was collected during the first presentation. A serial sample collected during remission 4 years later remains positive, albeit with a reduced ΔMFI. (C) Patient 2 similarly experienced 2 episodes of BON (normal MRI brain). The first sample was collected within 1 month of his relapse; a serial sample 4 months later during remission remained seropositive. (D) Patient 3 experienced 4 episodes of recurrent unilateral ON (MRI brain normal) affecting both eyes and was treated on 2 occasions with pulsed steroids. While the first serum sample within 1 month of her fourth relapse showed elevated MOG antibodies, 6-year follow-up revealed no further ON episodes and a ΔMFI below the positive threshold at remission. (E) Patient 4 presented with sequential BON and longitudinally extensive transverse myelitis (LETM) (MRI brain normal) and received aggressive immunotherapy. While his visual acuity has improved, he continues to experience moderate visual field deficits and has residual motor and sphincter disability related to spinal involvement. Serial samples were collected at initial presentation, during his relapse, and during remission. He remains seropositive more than 8 months after presentation. Ab = antibody; BON = bilateral and/or recurrent optic neuritis; MFI = mean fluorescence intensity; MMF = mycophenolate mofetil; MOG = myelin oligodendrocyte glycoprotein; MP = Intravenous methylprednisolone; PE = plasma exchange.
Figure 3
Figure 3. MOG antibody–associated BON has the potential to result in long-term visual impairment
(A) Visual functional system scores for MOG antibody–positive patients taken at the time of acute presentation and at latest follow-up demonstrate that the majority of patients experienced an improvement in visual acuity at follow-up. (B) Visual field deficits in 5 patients in both left (OS) and right (OD) eyes as measured by the mean deviation also demonstrate improvement at latest follow-up and approach the normal range (gray region between red lines, 0 to −3 dB). (C) The majority of affected eyes had a moderate to severe visual field deficit at onset but experienced an improvement in these scores. However, 2 affected eyes had a moderate residual deficit at latest follow-up. (D–G) Optical coherence tomography allowed for estimation of average peripapillary retinal nerve fiber layer (RNFL) thickness. During an acute episode of optic neuritis, swelling results in increased RNFL thickness (F). With resolution of the attack, RNFL thickness can either return toward the normal range (shaded region) (D) or result in RNFL thinning (E and G). Ab = antibody; BON = bilateral optic neuritis; MOG = myelin oligodendrocyte glycoprotein.
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