Post COVID-19 Myelin Oligodendrocyte Glycoprotein Antibody-Associated Optic Neuritis

ABSTRACT

Neurological manifestations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are relatively common. Although some may be consequences of direct cellular viral invasion (neurotropism), many represent post-infectious inflammation mediated by autoimmune mechanisms. We herein report the case of a 69-year-old diabetic male who presented with bilateral sub-acute, progressive loss of vision 45 days after suffering a presumed SARS-CoV-2 related pneumonia. He had bilateral optic disc oedema. Magnetic resonance imaging showed uniform contrast enhancement of both optic nerves without spinal cord involvement. He tested positive for SARS-CoV-2 IgG and myelin oligodendrocyte glycoprotein (MOG) IgG antibodies. He was treated with intravenous methylprednisolone for 5 days. The optic disc oedema resolved within 6 weeks with improvement in visual acuity, although optic atrophy developed by week 16. The MOG-IgG antibody test turned negative after 24 weeks.

Introduction

The novel global pandemic, coronavirus disease 19 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in late 2019. SARS-CoV-2 is an encapsulated single-strained RNA virus that belongs to the Beta-coronavirus genus, included in the Coronaviridae family. It is known to cause mainly flu-like symptoms and mild acute respiratory disease, whereas some patients remain asymptomatic.¹ However, about 20% of patients have more serious illnesses characterised by pneumonia, multi-organ failure, and in some cases, death.¹ With the spread of the pandemic, there is growing literature reporting other complications following SARS-CoV-2, including cardiac, gastrointestinal, neurological, ophthalmological and dermatological.²

Neurological complications following SARS-CoV-2 occur in up to one-third of patients. The manifestations reported include encephalopathy, encephalomyelitis, anosmia, ageusia, cranial nerve disorders (loss of vision, diplopia, and facial palsy), and neuromuscular diseases.^1,3 The incidence of neurological complications seems to be higher in cases of severe infection. Their presence is associated with a poor prognosis.⁴ Neurological involvement could be the consequence of direct viral invasion of neuronal and glial cells (neurotropism) or may be related due to para-infectious or post-infectious inflammation of the nervous tissue or its blood supply.³

We describe a case of a 69-year-old male with an acute respiratory syndrome due to SARS-CoV-2, who presented with post-infectious bilateral optic neuritis with positive myelin oligodendrocyte glycoprotein (MOG) IgG antibodies.

Case description

A 69-year-old male who had type II diabetes mellitus presented with a 15-day history of persistent fever (despite antipyretic treatment), rhinorrhoea and a mild expectorant cough. Upon arrival at the emergency room (ER), he was afebrile and his vital signs were normal. He denied chest pain, shortness of breath or changes in taste or smell. Blood tests revealed high levels of C-reactive protein (CRP) (11.72 mg/dL), lactate dehydrogenase (357 IU/L), D-dimer (779 ng/mL) and ferritin (1705 ng/mL). His renal function was normal (creatinine 1.01 mg/dL). A multi-lobar reticulo-nodular pattern was evidenced in the right lung on a chest radiograph. Due to the known pandemic context, a qualitative real-time reverse polymerase chain reaction (RT-PCR) diagnostic test for SARS-CoV-2 from a nasopharyngeal swab was performed, which turned out to be negative. Nevertheless, he was treated as COVID-19 and completed a 5-day course of oral antibiotic treatment with azithromycin (500 mg/day) and cefuroxime (2 g/day) in addition to oral hydroxychloroquine (400 mg/day), according to the therapeutic protocol established at that time. He was discharged home being afebrile, asymptomatic and with a basal oxygen saturation of 98%.

About 45 days later, he presented again to the ER with bilateral sub-acute, progressive loss of vision and pain on eye movements. He denied fever, headache, double vision or any other neurological symptoms. His blood pressure (124/77 mmHg) and basal oxygen saturation (99%) were normal. The cardiopulmonary and neurological examination were unremarkable. Ophthalmological assessment revealed a best corrected visual acuity (BCVA) of 20/60 in his right eye (OD) and 20/30 in his left eye (OS) with a relative afferent pupillary defect OD. His extra-ocular movements, anterior segment and intraocular pressure were all normal. Dilated fundus examination revealed bilateral disc oedema without macular, vascular anomalies or associated diabetic retinopathy (Figure 1a).

Figure 1.

Initial presentation: (a) Colour fundus photographs of both eyes revealing bilateral optic disc oedema. (b) Optical coherence tomography showing increased retinal nerve fibre layer thickness in both eyes. (c) Fluorescein angiography revealing dye leakage in both optic discs.

Visual field testing revealed generalised depression in both eyes with low reliability indexes (Figure 2a). Optical coherence tomography (OCT) showed a generalised increase in the thickness of the peripapillary retinal nerve fibre layer (pRNFL) in both eyes (Figure 1b). Fluorescein angiography revealed dye leakage in both optic discs (Figure 1c).

Figure 2.

(a) 30–2 visual field 30–2 showing generalised reduction of sensitivity in both eyes. (b) 30-2 visual field 6 weeks later showing an inferior altitudinal defect in the right eye and no significant deficit in the left eye.

Magnetic resonance imaging (MRI) of the brain and orbits showed extensive and uniform contrast enhancement of both optic nerves and sheaths (Figure 3). MRI of the spine was normal.

Figure 3.

Fat-suppressed post-gadolinium T1-weighted axial magnetic resonance imaging of the orbits showing thickening and enhancement of both optic nerves and sheaths, without optic chiasm involvement.

Routine blood tests were normal as well as CRP (0.08 mg/dL) and erythrocyte sedimentation rate (15 mm/h). Rheumatoid factor, anti-nuclear, anti-double stranded deoxyribonucleic acid, anti-neutrophil cytoplasm, anti-Ro, anti-La, anti-SCL 70, anti-Jo, anti-P, anti-Sm, and anti-chromatin antibodies were normal. Serologies for syphilis, Toxoplasma, Borrelia, Hepatitis B and C, and HIV were negative, however IgG antibodies against SARS-CoV-2 were detected by a qualitative chemiluminescence enzyme immunoassay. The decreased level of vitamin D was detected as an incidental finding, and supplementation was initiated. Cerebrospinal fluid (CSF) examination revealed a normal opening pressure of 12 cmCSF with normal levels of white blood cells (2/μL), glucose (65 mg/dL) and protein (27 mg/dL). Culture and viral serologies in the CSF were negative (including RT-PCR for SARS-CoV-2). Aquaporin 4 (AQP4) IgG was negative in both serum and CSF, however MOG-IgG was positive in serum but negative in CSF. Both were tested using cell-based assays (immunofluorescence on transfected HEK293 cells).

He was treated with intravenous methylprednisolone (1 g/24 h for 5 days) followed by an oral prednisone taper. After 5 days of treatment, his BCVA improved to 20/30 OD and 20/25 OS. His optic discs became less swollen and OCT showed a decrease in the thickness of the pRNFL.

Outpatient follow-up 6 weeks later revealed resolution of the optic disc oedema with incipient pallor of the temporal neuroretinal rim especially OD (Figure 4a); however, the pRNFL thickness on OCT was within normal limits in both eyes (Figure 4b). Visual field examination was now normal OS but there was a persisting inferior altitudinal defect OD (Figure 2b). After 16 weeks of follow-up, pallor of both optic nerve heads was observed (Figure 5a) and, on OCT, thinning of the pRNFL was present (Figure 5b). At his last review, 24 weeks after onset, BCVA was 20/30 OD and 20/25 OS with stable visual fields and no progression of optic atrophy. A further MRI was now normal. A MOG-IgG test assay was repeated and was now negative.

Figure 4.

After 6 weeks. (a) Colour fundus photograph showing resolution of optic disc oedema in both eyes. (b) Optical coherence tomography showing normal peripapillary retinal nerve fibre layer thickness in both eyes.

Figure 5.

After 16 weeks. (a) Colour fundus photograph showing mild pallor in both optic discs. (b) Optical coherence tomography revealing atrophy of the peripapillary retinal nerve fibre layer in both eyes.

Discussion

Several neuro-ophthalmological complications of COVID-19 have been described, which have been isolated or as part of a more generalised neurological syndrome.^1,3 They have included ocular pain, headache, ischaemic strokes, visual loss, diplopia, pupillary defects, ocular cranial nerve palsies, facial nerve diplegia and nystagmus.^5,6 Some of them may have been simply coincidental, or as a consequence of organ failure or metabolic abnormalities caused by the infection.⁴ However, several plausible mechanisms of neurological injury have been postulated, including direct viral invasion, endothelial dysfunction or a heightened inflammatory response.^5,7

The SARS-CoV-2 spike glycoprotein (S) mediates the virus entry into host cells and facilitates its replication. This interaction is the primary determinant for tissue tropism.⁷ It binds with high affinity to the host cellular angiotensin-converting enzyme 2 (ACE2) receptor,^4,7 which is present in the cell membranes of multiple organs (lung, vascular endothelium, kidney, intestine and smooth muscle), and normally regulates blood pressure and vasoconstriction.⁴ The expression of this ACE2 receptor has also been found in neurons and glial cells of numerous neural structures, such as the cerebral cortex, striatum, posterior hypothalamus, substantia nigra and brainstem.⁶

SARS-CoV-2 may have neuroinvasive and neurotropic capacities.⁵ Several possible viral access routes to the nervous tissues have been proposed: 1) the transcranial route (infection of olfactory epithelium and later transmission to the arachnoid space); 2) axonal transport and transynaptic transfer (includes the infection of peripheral and cranial nerves such as the trigeminal and vagus nerves); and 3) haematogenous or lymphatic invasion.⁶ Neurological manifestations could be the result of a direct neuronal cytopathic effect and a secondary activation of the microglia that triggers inflammation.^5,6 The bilateral optic neuritis of our patient could have been caused directly by viral infection, such as occurs in herpes viruses, arboviruses and other various viruses (mumps, influenza, rubella and measles).⁸ However, there was a period of 45 days between the SARS-CoV-2 infection and the optic nerve involvement, making it unlikely that it could be related to a direct viral infection. In addition, the CSF SARS-CoV-2 RT-PCR was negative which supports the absence of viral neurotropism at that moment.

Additional disorders with neuro-ophthalmological implications have been related to typical COVID-19 infection including Fisher syndrome; Guillain-Barré syndrome, Kawasaki disease, anti-phospholipid antibody syndrome; and neuromyelitis optica spectrum disorder (NMOSD).^1,5,9 They represent para-infectious or post-infectious autoimmune disorders, which could be triggered by virus infection, since SARS-CoV-2 can induce dysregulation of the immune system. The exact aetiology of autoimmune diseases remains unclear, but it is assumed that there is a genetic predisposition and environmental triggers, such as infections. There are viruses with known immuno-pathogenicity, such as parvovirus B19, Epstein-Barr virus, herpes virus 6, human T-lymphotrophic virus, hepatitis A and C virus and rubella virus.⁸ These viruses have the ability to trigger an autoimmune response through molecular mimicry and bystander mechanism activation (autoreactive immune T cells).^2,10 Structurally similar viral antigens from SARS-CoV-2 may have incited a host immune response against endogenous MOG in our patient.⁹ When circulating MOG antibodies enter the central nervous system (CNS) through disruption of the blood-brain barrier, pathology is mediated by T cells and activated complement, producing various clinical disorders, such as optic neuritis, transverse myelitis and acute disseminated encephalomyelitis (ADEM).²

Although the RT-PCR testing from the nasopharyngeal swab was negative in our patient, COVID-19 was presumptively diagnosed due to highly compatible respiratory symptoms and radiological manifestations at the time of the epidemic outbreak in Spain. This RT-PCR result is likely to have been a false negative, since it is known that the sensitivity of the RT-PCR test can range from 71 to 98%, although it can improve with repeat testing.10 However, the subsequent appearance of specific serum antibodies against SARS-CoV-2 did support this earlier clinical diagnosis. In our case, bilateral optic neuritis with anti-MOG positivity occurred after SARS-CoV-2 infection, but not immediately. Aside from an unlikely direct infection, an immune demyelinating mechanism triggered by the virus is the most plausible cause. NMOSD is an inflammatory demyelinating disorder of CNS that typically involves the optic nerve and spinal cord.¹¹ Positive serum AQP4-IgG and even MOG-IgG antibodies were described as biomarkers of NMOSD, playing a definite role in its diagnosis.¹¹ Recent literature has considered MOG-IgG associated disorder (MOGAD) as a new and independent immune-mediated inflammatory condition of the CNS, due to its distinctive pathophysiology and clinical features.¹² Patients with MOG autoimmunity may present with optic neuritis or transverse myelitis (NMOSD-like phenotypes), but also ADEM and cortical encephalitis. MOGAD can occur in all decades of life, with a median age of onset of 31 years.⁹ ADEM is the most common presentation in children and optic neuritis is in adults.^9,12 MOG-IgG optic neuritis should be suspected in cases that are bilateral, recurrent, steroid dependent, and especially if there is optic nerve head oedema or perineural enhancement in MRI.^9,12 Vision loss is severe at nadir, but the outcome is usually better than AQP4-IgG-positive optic neuritis.¹² Systemic infections are often associated with the onset and relapses of MOGAD. Thus, this fact would not be specific to COVID-19 since previous infections have been reported in 37.5–67% of patients with optic neuritis associated with MOG antibodies.¹³

To the best of our knowledge, there are at least three previous reported cases of MOG-IgG antibody mediated CNS disease associated with SARS-CoV-2 infection. Zhou et al. reported a case of a young Hispanic man with bilateral sequential vision loss associated with optic disc oedema, long segment bilateral neuritis and myelitis in MRI.² The patient reported a dry cough a few days before the onset of vision loss. De Ruijter et al. reported a case of a 15-year-old boy with bilateral vision loss and swollen optic discs.¹¹ MRI revealed bilateral optic neuritis without spinal cord involvement. A few weeks before presentation, he had been ill with a cough, nausea, and fever for about 10 days and he tested positive for SARS-CoV-2. Khan et al. described a case of a 11-year-old boy who presented with redness and ophthalmodynia in both eyes.¹⁴ Two weeks later he had overnight vision loss OD with optic disc oedema. A SARS-CoV-2 nasopharyngeal swab was positive as was a test for serum MOG-IgG antibodies.

Our patient did not develop myelitis or any other neurological symptoms. The age of presentation was significantly higher than that reported for the other COVID-19 patients with MOG-IgG optic neuritis.^2,11,14 Anterior ischaemic optic neuropathy (NAION) is painless, has optic disc oedema, causes altitudinal visual defects and is usually seen in patients older than 50 years.¹² MOG-IgG optic neuritis can mimic the disc appearance of NAION.¹² However, the lack of an abrupt onset, bilateral and painful presentation, enhancement of the optic nerves on MRI and absence of small discs or a hypercoagulable state all argue against an ischaemic aetiology. In our patient, the initial visual loss was moderate and quite symmetrical, although somewhat greater OD. There was also rapid visual recovery with corticosteroid treatment.

In conclusion, the complete spectrum of neuro-ophthalmological complications associated with SARS-CoV-2 infection has not been fully identified, as far as new symptoms and signs are continually being described. We have described a case of bilateral and simultaneous optic neuritis with MOG antibodies in a 69-year-old man after previous SARS-CoV-2 infection. The transient positivity of MOG antibodies associated with optic neuritis was likely caused by an autoimmune mechanism triggered by the virus.

Funding Statement

The authors received no financial support for the research, authorship, and/or publication of this article.

Patient consent

The patient provided written informed consent for the use of his medical history and images in this publication.

Declaration of interest statement

No potential conflict of interest was reported by the author(s).