Chronic relapsing inflammatory optic neuropathy (CRION): a manifestation of myelin oligodendrocyte glycoprotein antibodies

A total of 615 consecutive patients identified between 2011 and 2017 with IDDs of the CNS were screened from the prospectively collated database of Seoul National University’s Multiple Sclerosis/Neuromyelitis Optica Center in South Korea. The diagnosis, clinical characteristics, and laboratory findings of patients were reviewed by HJL and SMK. Patients with acute visual symptoms were evaluated by an experienced neurologist and an ophthalmologist. A diagnosis of ON was made on the basis of acute visual symptoms such as decreased visual acuity or visual field defect and evidence of an afferent pupillary defect in the affected eye. MRI imaging and blood sampling were performed. Of the 214 patients with symptomatic ON, patients with multiple sclerosis [6], neuromyelitis optica spectrum disorder (NMOSD) with or without AQP4-IgG [7], acute disseminated encephalomyelitis [8], and patients with symptomatic CNS lesions other than on the optic nerve were excluded from this study. The remaining patients, who were not excluded, were diagnosed as isolated ON. Ninety patients with iON were identified. Subsequently, patients who had incomplete ophthalmological data, e.g., missing optic disc evaluation, measurement of visual acuity, or visual field examination, patients with no AQP4-IgG or MOG-IgG1 assay results or available serum samples, and patients who were followed for less than 6 months were also excluded (Fig. 1). Assays for AQP4-IgG were performed by an in-house fluorescence-activated cell sorting (FACS) assays using live cells expressing human M23 AQP4, as described previously [9, 10]. Finally, 64 patients with iON, seronegative for AQP4-IgG, were included in this study.

Patients were diagnosed with CRION according to recent criteria [2]. It requires at least one relapse, objective evidence for the loss of visual function, seronegative AQP4-IgG results, contrast enhancement of the optic nerve on MRI, response to steroid treatment, and steroid-dependent relapse [2].

Of the 64 sera from patients with iON, 33 sera were tested for serum IgG1 MOG-IgG by MW at John Radcliffe Hospital (Oxford, UK), using cell-based assays expressing full-length human MOG [11]; and 38 sera were tested at Seoul National University (Seoul, Korea) by BRK, using flow cytometry (FACS). Seven serum samples were tested at both locations. Epidemiological, clinical, and radiological data were blinded to both MW and BRK until the assays were completed. The flow cytometric MOG-IgG assays were performed with a minor modification from the previously published method [11]. Briefly, human embryonic kidney 293 T cells were transfected with a pcDNA3.1 vector (Invitrogen) containing full-length human MOG (α1, NM_206809.3) cDNA, using lipofectamine. Patient sera were tested at 1:50 dilution, and the mouse anti-human IgG1 Hinge-FITC (hinge) from SouthernBiotech (9052-02, Birmingham, AL) was used at 1:100 dilution. The geometric mean fluorescence (G-mean) ratio was calculated for each patient using the formula: G-mean values of the patient/G-mean values of the healthy control (Additional file 1). The cutoff was set to six standard deviations (SD) [12] above the average. The average G-mean ratio was calculated from 89 controls (39 patients with AQP4-IgG-positive NMOSD, 23 with multiple sclerosis, seven with malignancy, four with polyneuropathy, four with vascular disease, two with dermatomyositis, two with Churg-Strauss syndrome, and one each with CNS lupus, compressive myelopathy, fungal sinusitis, Leber’s hereditary optic neuropathy, neuro-Behcet’s disease, somatoform disorder, hereditary spastic paraplegia, and syringomyelia). As the average G-mean ratio of our 89 control sera was 0.98 ± 0.11 (0.25–1.23) {mean ± SD (minimum–maximum)}, a G-mean ratio above 1.64 was considered positive for MOG-IgG1-Abs. The G-mean ratio values between the highest values of the controls and cutoff values (1.23–1.64) were considered to be a borderline result. Among our 64 patients with iON, the percent positivity of the MOG-IgG assay was similar between Oxford and Seoul, at 39% (13/33) and 32% (12/38), respectively (seven sera were tested both in Oxford and Seoul with identical results).

A Snellen chart was used to measure the visual acuity (VA) and converted into logMAR for analysis. Severe visual disability was defined as VA less than 20/200 at nadir. A favorable visual outcome was defined as VA more than 20/40 at final follow-up. Visual fields were examined within 1 month of the first ON attack using the Goldmann or Humphrey perimetry.

Retinal nerve fiber layer, ganglion cell-inner plexiform layer, and macula thicknesses were measured using spectral-domain optical coherence tomography (Cirrus HD OCT, Carl Zeiss Meditec, Inc., Dublin, CA, USA) at least 1 month after intravenous steroid pulse therapy.

MRI studies included axial, coronal, and sagittal images of the brain and spinal cord obtained using T1-weighted (W), T2-W, and T1-W fat suppression post-contrast sequences within 1 month of the acute attack. The presence of optic nerve enhancement on MRI was evaluated and analyzed by dividing the anatomical segments of the optic nerve into orbital, canalicular, intracranial, chiasmal, and optic tract regions [13]. On axial images, the proportion of optic nerve enhancement in the orbital area was calculated as follows: the length of enhancement at the maximum length of the orbital optic nerve divided by the maximum total length of the optic nerve in the orbital area. Perineural enhancement [4], defined as extensive enhancement to the soft tissues surrounding the intraorbital portion of the optic nerve, was also evaluated.

All patients received intravenous methylprednisolone (250 mg every 6 h for either 3 or 5 days). At the discretion of clinicians, oral prednisone was administered and tapered after IV steroid pulse treatment. The average duration of oral steroid use was 34.4 ± 31.8 days. A good response to steroid therapy was defined as the recovery of VA to more than 20/40, within 1–2 months, after steroid pulse therapy. Steroid dependency, based on previously reported characteristics of CRION [1], was defined as a relapse or exacerbation of ON, occurring within 2 months from the time of cessation or dose reduction of steroid treatment. Relapse was defined as a new ON episode lasting at least 24 h. During the follow-up period, the total number of ON attacks and the time interval between attacks were evaluated.

The study was approved by the Institutional Review Board of Seoul National University Hospital in Korea (approval number H-1012-080-344). The study protocol followed the tenets of the Declaration of Helsinki.

Sixty-four patients with iON were included in the present study (Fig. 1). The mean age of the first ON attack was 42.5 ± 16.6 years. Thirty-six patients (56%) were females. The mean time interval between onset of ON and steroid treatment was 6.5 ± 2.5 days. The total average number of ON attacks was 1.8 ± 1.3 during the total follow-up duration of 39.5 ± 42.3 months (range 6–250). Twenty-six patients had relapsing disease courses, and 38 had monophasic courses.

Of the 26 patients with recurrent iON, 12 patients fulfilled the current diagnostic criteria for CRION; 11 patients were positive for MOG-IgG, and 1 patient was borderline (average G-mean ratio 4.1, range 1.59–7.87) (Additional file 2). Fourteen patients with relapsing iON did not meet the criteria for CRION, due to the absence of either relapse on withdrawal or dose reduction of steroid treatment (n = 14), lack of response to steroid treatment (n = 6), or absence of contrast enhancement of the optic nerve on MRI (n = 7) (Table 1). Among the subcriteria for CRION, the presence of the steroid dependency (relapse on withdrawal or dose reduction of steroid) had the highest positive predictive values (91.7%) for MOG-IgG positivity (Fig. 2).

Patients with iON (n = 64) were classified into three groups according to their courses and characteristics of ON [2, 14, 15]: (1) CRION (n = 12), (2) recurrent idiopathic ON (RION) (n = 14), and (3) monophasic idiopathic ON (monophasic iON) (n = 38). MOG-IgG positivity was 92% in patient with CRION, 0% in patients with RION, and 29% in patients with monophasic iON (Fig. 3).

Of the 11 CRION patients with MOG-IgG (CRION-MOG+ group), seven (64%) were females. The mean age of the first ON attack was 41.4 ± 12.8 years (range 20.8–62.1). Optic disc swelling was present in 33% of the patients. Pain with eye movement was presented in 82% of the patients, and a VA less than 20/200 at nadir was present in 80% of the patients. Perineural enhancement of the optic nerve was present in 71% of the patients.

Of the 52 patients who did not meet the criteria for CRION, 11 tested positive for MOG-IgG (non-CRION-MOG+ group). In contrast to the CRION-MOG+ group who all had relapsing disease courses, our non-CRION-MOG+ patients had only monophasic disease courses. The CRION-MOG+ group experienced steroid-dependent worsening/relapse in the early stages of the disease (2.3 months from disease onset). The CRION-MOG+ group had more frequent ON attacks, and thinner retinal nerve fiber layer and ganglion cell-inner plexiform layer thicknesses, than the non-CRION-MOG+ group. The duration of oral immunosuppressive treatment after first attack did not differ significantly between the groups (Table 2).