Delayed Diagnosis of Anti-Myelin Oligodendrocyte Glycoprotein One Decade After Presumed Recurrent Acute Disseminated Encephalomyelitis

Clinical Correspondence Section Editors: Robert Avery, DO Karl C. Golnik, MD Caroline Froment, MD, PhD An-Guor Wang, MD Delayed Diagnosis of Anti–Myelin Oligodendrocyte Glycoprotein One Decade After Presumed Recurrent Acute Disseminated Encephalomyelitis Jason Zehden, Shruthi Harish Bindiganavile, MD, Nita Bhat, MD, Andrew G. Lee, MD, Robert Avery, DO, Karl C. Golnik, MD M yelin oligodendrocyte glycoprotein (MOG) antibody–associated disorder (MOGAD) is a central nervous system inflammatory disorder which has protean manifestations (1). MOGAD is associated with presence of serum antibodies directed against MOG (MOG-IgG), but their pathogenicity remains to be proven (1). The disorder may be confused with multiple sclerosis (MS), aquaporin-4 antibody neuromyelitis optica spectrum disorders (AQP4-IgG NMOSD), and acute disseminated encephalomyelitis (ADEM) (1). Since the discovery of MOGAD and recognition of the wide clinical spectrum is recent, patients with MOGAD may incorrectly carry the diagnosis of “atypical” MS or ADEM. We describe a patient with an 11-year time span from initial multiple incorrect diagnoses to a final diagnosis of MOGAD. A 23-year-old Hispanic man presented 9 years earlier at age 14 years with altered mental status, gait instability, vertigo, urinary retention, and constipation after receiving a vaccination. At this time, he had acute-onset pain with eye movements and bilateral vision loss consistent with optic neuritis in both eyes. On examination, bilateral disc edema was present. MRI of the brain, orbits, and spine demonstrated multifocal, bilateral asymmetric basal ganglia and thalami lesions. There was no appreciable optic nerve or perineural enhancement or signal change. Cerebrospinal fluid (CSF) analysis showed 51 white blood cells/mm3 (normal ,5) elevated protein at 66 g/dL (normal ,50) and normal CSF glucose. He was diagnosed with ADEM and Baylor College of Medicine (JZ, SHB, AGL), Houston, Texas; Department of Ophthalmology (AGL, NB), Blanton Eye Institute, Houston Methodist Hospital, Houston, Texas; Houston Methodist Research Institute (AGL), Houston Methodist Hospital, Houston, Texas; Departments of Ophthalmology (AGL), Neurology, and Neurosurgery, Weill Cornell Medicine, New York, New York; Department of Ophthalmology (AGL), University of Texas Medical Branch, Galveston, Texas; University of Texas MD Anderson Cancer Center (AGL), Houston, Texas; Texas A and M College of Medicine (AGL), Bryan, Texas; and Department of Ophthalmology (AGL), the University of Iowa Hospitals and Clinics, Iowa City, Iowa. The authors report no conflicts of interest. Address correspondence to Andrew G. Lee, MD, Blanton Eye Institute, Houston Methodist Hospital, 6560 Fannin Street, Suite 450, Houston, TX 77030; E-mail: [e-mail] Zehden et al: J Neuro-Ophthalmol 2022; 42: e469-e472 had complete neurologic recovery with intravenous (IV) methylprednisolone 1,000 mg daily treatment. He improved so rapidly with IV steroid treatment that by the time he was discharged from the hospital, his visual symptoms had resolved, and he only had mild dysmetria, gait instability, and hyperreflexia. The next year, a follow-up MRI showed punctate signal abnormalities in the cerebellar hemispheres with residual areas of nonenhancing gliosis and demyelination. Four years later, at age 18, he had acuteonset pain with left eye movement and left eye vision loss consistent with another episode of optic neuritis. Examination revealed a visual acuity of 20/20 in the right eye and 20/200 in the left eye. There was a left relative afferent papillary defect (RAPD) and normal disc appearance in both eyes. The lack of disc edema may have been due to pallor masking the edema. MRI brain with contrast demonstrated progressive signal change in the subcortical white matter at the right parietal lobe extending to the right posterior temporal and occipital area with progressive enhancement in these areas. MRI orbit showed bilateral symmetric appearance of hazy, nonenhancing T2 lesions of the optic nerves. MRI of the cervical and thoracic spine was normal. CSF analysis showed no pleocytosis, proteins, or oligoclonal bands. After 5 days of IV methylprednisolone 1,000 mg daily, his vision completely recovered. At age 20, he developed a seizure disorder secondary to ADEM and was diagnosed with “recurrent ADEM.” At age 23, he had a recurrent optic neuritis in the left eye characterized by painful left eye movement and vision loss. Repeat MRI of the brain showed no new demyelinating lesions. MRI of the orbits demonstrated increased T2 signal and mild enhancement of the bilateral optic nerves, most pronounced on the left. Testing for AQP4-IgG was negative, and at that time, his diagnosis was changed to “atypical MS” and he was started on treatment with interferon beta-1a. He was then seen by our neuro-ophthalmology service 1 year after his last optic neuritis attack. On examinatiom, visual acuity was 20/20 in the right eye and 20/25 in the left eye and color plates were 14/14 and 1/14. His pupils measured 4 mm in dark and 2 mm in light, with a left RAPD. Slit-lamp examination was normal. e469 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence GAD, the patient remained stable on this regimen with no recurrence of neurologic deficit or visual loss. DISCUSSION FIG. 1. Humphrey visual field 24-2 testing showing bitemporal visual field defects. Humphrey visual field testing showed a bitemporal field defect with a mean deviation of 25.58 dB (dB) in the left eye and 26.13 in the right eye cecocentral scotoma in the left eye (Fig. 1). Optical coherence tomography revealed retinal nerve fiber layer consistent with optic atrophy in both eyes (Fig. 2). Anti-MOG-IgG testing was unavailable until 2 years later, when the patient was 25, and it was positive with a titer of 1:100 (normal ,1:20). He was switched from immunomodulatory therapy for MS to an immunosuppressive regimen for MOGAD with mycophenolate mofetil. At last follow-up, 18 months after being diagnosed with MO- MOGAD can mimic monophasic ADEM, recurrent ADEM, seronegative NMO, or MS. The interesting finding in this case is the long (11-year) time interval between the initial diagnosis of “ADEM” and the ultimate diagnosis of MOGAD. In retrospect, several features of this case suggested MOGAD including the patient’s non-Caucasian ethnicity, male sex, recurrent steroid responsive optic neuritis, atypical white matter lesions for MS, initial presentation with presumed monophasic ADEM, followed by “recurrent ADEM” and then “atypical MS.” Although MOGAD is a relatively recent diagnosis, the patient’s “atypical MS” should have prompted a workup for mimics of MS. In contrast to MS, MOGAD often presents in childhood and can mimic both ADEM and NMOSD (2). Unlike MS and AQP4-IgG NMOSD, MOGAD has no racial or sex predilection (1). The variable manifestations of MOGAD include optic neuritis, ADEM, transverse myelitis, or cortical encephalitis (1,2). Clinical and imaging findings of MOGAD can also overlap with seronegative NMOSD (1). Overall, optic neuritis is the most common attack in MOGAD, but ADEM is the most common attack in children and relapses are most commonly in the form of optic neuritis (3). About 60% of children with ADEM have MOG-IgG, and the continued presence of MOG-IgG in FIG. 2. Optical coherence tomography showing bilateral optic atrophy. OD, right eye; OS, left eye. e470 Zehden et al: J Neuro-Ophthalmol 2022; 42: e469-e472 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence children may suggest a higher tendency toward relapses of optic neuritis or of ADEM (1,4). Patients with ADEM, multiphasic disseminated encephalomyelitis, simultaneous or sequential bilateral optic neuritis, transverse myelitis, optic neuritis with papillitis, recurrent optic neuritis, and longitudinally extensive transverse myelitis and brainstem/ cerebral cortical encephalitis must be considered to be tested for MOG-IgG (1). There are unique MRI findings that differentiate MOGAD from MS and AQP4-IgG NMOSD. Orbital MRI in MOGAD commonly shows lesions involving the orbital segment of the optic nerve, while chiasm and optic tract lesions are more likely observed in AQP4-IgG NMOSD and less commonly seen in MOGAD (5,6). In addition, the presence of bilateral optic neuritis especially with perineural enhancement differentiates MOGAD from MS-related optic neuritis (5). The average length of the enhancing optic nerve lesions was found to be longest in MOGAD with an average length of 20.5 mm as compared with 17.6 mm in AQP4-IgG NMOSD, and both disorders demonstrated enhancement that is longer (longitudinally extensive) than typical MS lesions (7). The most frequently involved brain lesions observed on MRI in MOGAD are in the deep white matter (5). The focal, discrete, nodular callosal lesions without a specific orientation around the ventricles in MOGAD patients is reported to be distinct from the classic Dawson finger-type pattern observed in MS or the arch of the bridge sign in AQP4-IgG NMOSD (5). MOGAD has less spinal cord and brain involvement compared with AQP4-IgG NMOSD and MS (8). It is more common to observe normalization of the T2 signal on MRI in MOGAD than AQP4-IgG NMOSD (9). MRIs of patients with MOGAD normally show resolution of previously noted demyelinating lesions and absence of new brain lesions outside of relapse (1). Treatment of acute relapses of MOGAD involves highdose steroids for 3–7 days (1). After the initial attack, patients benefit from a slower and longer taper of oral steroids compared with MS. A repeat testing of MOG-IgG may be performed at the end of steroid taper (1,2). Negative MOG-IgG may indicate remission (1,2). Only 50% of patients relapse after an initial attack (10). Even if MOGIgG is persistently positive, which is the case in most patients, most experts would recommend observation without chronic immunotherapy after a single attack since most patients continue to be positive and many remain monophasic (10). Patients with persistent MOG-IgG who relapse should be considered for chronic immunosuppression (e.g., rituximab, azathioprine, and mycophenolate) (10). IV immunoglobulin (IVIG) also has shown promise as a chronic immunotherapy in MOGAD (11). Similar to AQP4-IgG NMOSD, treatment of MOGAD with MS medications such as interferon-beta-1-alpha has been found to have no or rarely harmful effects, although there are few studies assessing this in MOGAD (12). Zehden et al: J Neuro-Ophthalmol 2022; 42: e469-e472 In summary, it is worthwhile to test for MOG antibodies in any patient who presents with recurrent optic neuritis, steroid-responsive or steroid-dependent optic neuritis, and especially if they have had history of childhood ADEM. As observed from a study by Lopez-Chiriboga et al, many patients with MOGAD have long periods between disease attacks (as much as 23 years) (13). As demonstrated by our case report, the study by Lopez-Chiriboga et al, and with MOG-IgG testing only being commercially available in the United States since the end of 2017, physicians must keep MOGAD in mind and consider testing for any patient with a remote history of optic neuritis, ADEM, or other demyelinating attacks consistent with MOGAD. We now routinely check for MOG-IgG in these patients regardless of duration from initial diagnosis. To the best of our knowledge, this is the longest duration from initial diagnosis to final diagnosis of seropositive MOGAD in the English language ophthalmic literature. STATEMENT OF AUTHORSHIP Category 1: a) Conception and design: J. Zehden, S. H. Bindiganavile, and A. G. Lee; b) acquisition of data: J. Zehden and S. H. Bindiganavile; c) analysis and interpretation of data: J. Zehden, S. H. Bindiganavile, A. G. Lee, and N. Bhat. Category 2: a) Drafting the manuscript: J. Zehden, S. H. Bindiganavile, and A. G Lee; b) revising it for intellectual content: J. Zehden, S. H. Bindiganavile, and A. G. Lee. Category 3: a) Final approval of the completed manuscript: S. H. Bindiganavile and A. G. Lee. REFERENCES czyk M, Jacob A, Fujihara K, Palace J. Myelin 1. Juryn oligodendrocyte glycoprotein (MOG) antibody-associated disease: practical considerations. Pract Neurol. 2019;19:187– 195. 2. Reindl M, Waters P. Myelin oligodendrocyte glycoprotein antibodies in neurological disease. Nat Rev Neurol. 2019;15:89–102. 3. de Mol C, Wong Y, van Pelt E, Wokke B, Siepman T, Neuteboom R, Hamann D, Hintzen RQ. The clinical spectrum and incidence of anti-MOG-associated acquired demyelinating syndromes in children and adults. Mult Scler J. 2020;26:806– 814. 4. 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