1 DEPARTMENT OF OPHTHALMOLOGY
FACULTY OF MEDICINE PADJADJARAN UNIVERSITY NATIONAL EYE CENTER CICENDO EYE HOSPITAL BANDUNG
Case Report : Neuromyelitis Optica Spectrum Disorders as The First Neuro-Ophthalmic Manifestation of COVID-19: A Case Report
Presenter : Rizki Fasa Ramdhani Supervisor : Rusti Hanindya Sari, MD
Has been reviewed and approved by Supervisor of Neuro-Ophthalmology Unit
Rusti Hanindya Sari, MD
4th October 2021 7.30 AM
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abnormalities and others. Neuromyelitis optica spectrum disorders (NMOSD) is a type of inflammatory optic neuritis in which the autoimmune response can be triggered by viral infection.
Purpose To report a case of bilateral atypical optic neuritis related to NMOSD in COVID-19 patient.
Case Report A 54-year-old female presented with decrease vision on both eyes since 3 weeks. She also complained of having limb weakness and anosmia. She had history of fever and cough before the presentation. Her vital sign was within normal limit.
Ophthalmologic examination revealed visual acuity 1/300 on the right eye and no light perception on the left eye. Pupillary reflex was decreased on both eyes. Funduscopy examination showed bilateral optic disc swelling with peripapillary haemorrhage. Brain MRI with contrast showed hyperintense lesion of both optic nerves, optic chiasm and spinal cord C2-C5. The result of laboratory examination was elevated erythrocyte sedimentation rate, C-reactive protein, and D-dimer. Nasopharyngeal swab examination showed positive result for polymerase chain reaction COVID-19. She was diagnosed with bilateral atypical optic neuritis related to NMOSD with COVID-19. Visual acuity improvement was achieved after high dose intravenous methylprednisolone therapy.
Conclusion Post-infectious immune-mediated etiology may be the pathogenesis of optic neuritis in NMOSD. Comprehensive evaluation of patient with optic neuritis is important to confirm the possible etiology, including COVID-19 infection.
Keyword COVID-19, NMOSD, optic neuritis
I. INTRODUCTION
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported in December 2019 in Wuhan, China and the virus causing coronavirus disease 2019 (COVID-19). COVID-19 has spread rapidly around the world and declared as a pandemic in March 2020. Indonesia reported more than 4 million confirmed cases and more than one hundred thousand deaths because of COVID- 19. In early days of the pandemic, COVID-19 was primarily associated with respiratory symptoms such as cough, fever, shortness of breath, and respiratory failure. However, COVID-19 is not purely a respiratory disease, the virus may produce a wide spectrum of manifestations in any organ such as acute cardiac disease, acute kidney injury, vasculopathy, coagulopathy, elevated inflammatory markers, and neurological deficits.1-3
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COVID-19 has a wide spectrum of ocular manifestations from anterior to posterior segment. Optic neuritis is an inflammation of the optic nerve which can be caused by various etiology. Neuromyelitis optica spectrum disorders (NMOSD) is an inflammatory condition of the central nervous system (CNS), which is also known as Devic’s disease. It frequently affects the optic nerve and spinal cord. Core clinically symptoms are optic neuritis, acute myelitis, area postrema syndrome, and acute brainstem syndrome. The pathogenesis of NMOSD remains unknown but viral infections such as COVID-19 has been reported to trigger an autoimmune response in the development of NMOSD.4-6 This study reported a case of bilateral atypical optic neuritis related to NMOSD in COVID-19 patient.
II. CASE REPORT
A 54-year-old woman presented with blurred vision on both eyes, reported 3 weeks on the left eye (LE) and 1 week on the right eye (RE). Patient came to the clinic using a wheelchair because of weakness of the lower limb. There were no complains of headache, nausea and vomit. She and her family (husband and daughter) had history of flu-like symptoms, fever, and anosmia before admission.
The patient denied any history of head trauma, long-term medication, and systemic diseases.
Physical examination showed normal vital signs. Ophthalmological examination revealed visual acuity was 1/300 on RE and no light perception on LE. Intraocular pressure (IOP) was within normal limit. Hirschberg test showed esotropia, and no restriction of eye movement was documented. Anterior segment on both eyes showed decreased in direct and indirect pupillary light reflex. The posterior segment examination with indirect funduscopy revealed optic disc swelling with peripapillary haemorrhage on both eyes. Color vision, amsler grid, and contrast sensitivity examination were difficult to evaluate. Optical Coherence Tomography (OCT) showed increased in average retinal nerve fiber layer (RNFL) thickness on both eyes.
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Figure 1. (A) Eye movement of the patient showed no limitation with (B) fundus photography showed optic disc swelling with peripapillary haemorrhage and (C) optic
disc OCT showed increase in average RNFL thickness
The patient was diagnosed with suspected papilledema with differential diagnosis bilateral atypical optic neuritis caused by infection. Patient received oral methylprednisolone 1x56 mg, oral lansoprazole 1x30 mg, oral mecobalamin 1x500 mcg, and vitamin D3 supplement 2x400 IU. She was suggested to perform routine hematologic examination, erythrocyte sedimentation rate, C reactive protein, D-dimer, and nasopharyngeal swab polymerase chain reaction for COVID-19. We also suggested the patient to underwent neuroimaging studies.
The patient came one week after with slight improvement of vision.
Ophthalmologic examination showed visual acuity one-meter finger counting on RE and light perception on LE. The posterior segment evaluation revealed optic disc swelling with minimal peripapillary haemorrhage. There was an improvement of motoric strength.
Brain Magnetic Resonance Imaging (MRI) and Magnetic Resonance Angiography (MRA) showed hyperintense lesion on combination of optic neuritis and cervical myelopathy in the level of C2-C5, cerebral and cerebellar atrophy, old lacunar infarct in right and left pons (figure 3). There was an increased in
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eosinophil on differential count, elevated erythrocyte sedimentation rate, C reactive protein and D-Dimer (864.92 ng/mL). Nasopharyngeal swab showed positive result polymerase chain reaction COVID-19 with CT value 37.02.
Figure 3. Magnetic Resonance Imaging and Magnetic Resonance Angiography showed hyperintense lesion with involving optic chiasm and cervical myelopathy in the level of
C2-C5 and no aneurysm and thrombosis.
The patient was diagnosed with bilateral atypical Optic neuritis RLE caused by NMOSD with Covid-19 infection. High dose intravenous injection of methylprednisolone 4x250 mg, omeprazole iv 2x40mg, mecobalamin iv 1x500mcg, and COVID-19 therapy was administered to the patient. On the second day of hospitalization, nasopharyngeal swab results for COVID-19 were negative for COVID-19 and on the third day patient given anticoagulant (heparin) intravenous. Patient reported an improvement of her vision on the third day and was discharged after 12th doses of intravenous methylprednisolone administration. Treatment was continued with oral methylprednisolone 1 mg/kg BW/day (64 mg per day), tapered off every week, omeprazole 1x20 mg, Vit D3 tablet 1x5000 IU, mecobalamin tablet 1x500 mcg, rivaroxaban 1x10 mg, and N- acetylcysteine tablet 3x1.
Figure 4. On the folllow up visit, (A) fundus photography showed optic disc swelling, pallor, and ghost vessel in both eye and (B) Optic Disc OCT showed decreasing in swelling in both eye. (C) Humphrey Visual Field 30-2 showed central scotoma in both
eyes.
Ophthalmological examination showed improvement of visual acuity to 0.16 in both eyes on 3 weeks follow up. Posterior segment evaluation revealed bilateral optic disc slight swelling, pallor, and ghost vessel. Colour vision with Ishihara test results was demoplate in both eyes and MARS contrast sensitivity was 0.80log (severe) in the RE and 0.52log (severe) on the LE. The patient was consulted to the neurology department for further evaluation.
III. DISCUSSION
Severe acute syndrome coronavirus 2 is a beta coronavirus that cause a variety of symptoms in patients COVID-19. It is increasingly evident that COVID-19 has
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a wide range of neurological manifestations that can caused by central and peripheral nervous system lesion. Neuro-ophthalmic problems associated with COVID-19 that had been reported are optic neuritis, cranial nerve palsies, and eye movement abnormalities. There are several studies reported optic neuritis cases after COVID-19 infection. Azab et al reported that females were more affected by optic neuritis after COVID-19 infection.2,7,8 In this case, the patient is a female with COVID-19 symptoms before the visual complain started.
Table 1. NMOSD diagnostic criteria for adult patients Diagnostic criteria
for NMOSD with AQP4-IgG
1. At least 1 core clinical characteristic
2. Positive test for AQP4-IgG using best available detection method (cell- based assay strongly recommended)
3. Exclusion of alternative diagnoses Diagnostic criteria
for NMOSD without
AQP4-IgG or
NMOSD with
unknown AQP4-IgG status
1. At least 2 core clinical characteristics occurring as a result of one or more clinical attacks and meeting all of the following requirements:
a. At least 1 core clinical characteristic must be optic neuritis, acute myelitis with LETM, or area postrema syndrome
b. Dissemination in space (2 or more different core clinical characteristics) c. Fulfilments of additional MRI requirements, as applicable
2. Negative tests for AQP4-IgG using best available detection method, or testing unavailable
3. Exclusion of alternative diagnoses Core clinical
characteristics
1. Optic neuritis 2. Acute myelitis
3. Area postrema syndrome: episode of otherwise unexplained hiccups or nausea and vomiting
4. Acute brainstem syndrome
5. Symptomatic narcolepsy or acute diencephalic clinical syndrome with NMOSD-typical diencephalic MRI lesions
6. Symptomatic cerebral syndrome with NMOSD-typical brain lesions Additional MRI
requirements for NMOSD without AQP4-IgG and
NMOSD with
unknown AQP4-IgG status
1. Acute optic neuritis: requires brain MRI showing (a) normal findings or only nonspecific white matter lesions, OR (b) optic nerve MRI with T2- hyperintense lesion or T1-weighted gadolinium enhancing lesion extending over >1/2 optic nerve length or involving optic chiasm
2. Acute myelitis: requires associated intramedullary MRI lesion extending over ≥3 contiguous segments (LETM) OR ≥3 contiguous segments of focal spinal cord atrophy in patients with history compatible with acute myelitis
3. Area postrema syndrome: requires associated dorsal medulla/area postrema lesions
4. Acute brainstem syndrome: requires associated periependymal brainstem lesions
NMOSD: neuromyelitis optica spectrum disorder, AQP4-IgG: anti-aquoporin-4 immunoglobulin G, LETM: longitudinal extensive transverse myelitis, MRI: magnetic resonance imaging.
Source: Wingerchuk4
Neuromyelitis optica spectrum disorders (NMOSD) is an autoimmune disorder of central nervous system (CNS) associated with antibodies against aquaporin-4 (AQP4). Core clinical characteristic of NMOSD are optic neuritis, acute myelitis, area postrema syndrome, acute brainstem syndrome, symptomatic narcolepsy/acute diencephalic clinical syndrome, and symptomatic cerebral syndrome with MRI lesions. Diagnostic criteria by the International Panel for NMO Diagnosis (IPND) had been published by Wingerchuk et al (Table 1).4,8,9 This patient met the criteria NMOSD with unknown anti-aquaporin-4 immunoglobulin G (AQP4 IgG) status with optic neuritis and acute myelitis as the core clinical characteristics. MRI brain showed hyperintense lesion of optic nerve and optic chiasm. Cervical myelopathy at the level of C2-C5 (≥3 contiguous segments) showing Longitudinal extensive transverse myelitis lesions (LETM) was also confirmed.
The exact pathomechanism of COVID-19 with CNS involvement remain unknown. Viral dissemination to the CNS can be achieve by hematogenous spread from the systemic circulation or trans-neuronal spread through the olfactory pathway. Several mechanisms that has been postulated as the pathomechanism are (1) direct neurological damage when the virus reaches the nervous system and binds to angiotensin-converting enzyme 2 (ACE2) receptors. (2) Accumulation of proinflammatory cytokines that can cross the blood-brain barrier (BBB), activating innate immunity by the affected macrophages, microglia, and astrocytes, and creating cytokine storm. In NMOSD, IL-6 plays a crucial role in the stimulation of AQP4-IgG secretion, altering the integrity and function of BBB, and activating proinflammatory T-Lymphocytes. (3) formation of blood clots. (4) formation of autoantibodies against myelin, known as molecular mimicry.3,10,11 In COVID-19 associated with demyelination, viral infection can induce inflammatory response, activating myelin-specific T cells, and accelerate the development of early or delayed virus-induced demyelination. In this patient, bilateral optic neuritis occurs 3 weeks after the patient had first symptoms of presumed COVID-19. This might highlight the role of inflammatory factors after infection and delayed immune response rather than a direct invasion of the virus.
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COVID-19 had the same pathogenesis mechanism that involved the cytokines with the demyelinating disorder. NMOSD mostly has a relapsing course if left untreated. Accumulation of disability in NMOSD is associated with incomplete recovery from each relapsing attack, rather than secondary progression or degeneration. Treatment for NMOSD is management in acute attack to promote recovery, prevent relapse with long-term immunosuppressive treatment, prevention, and monitoring of adverse effects. Initial therapy with intravenous methylprednisolone (IVMP) at 1 gr per day for 3-5 consecutive days is the first- line treatment of acute attacks of NMOSD. The mechanism of action of corticosteroids are: (1) Inhibition of pro-inflammatory cytokine production, (2) downregulation of cell adhesion molecules and receptors expression, (3) augmentation of anti-inflammatory cytokine secretion, (4) reduction and modulation of T-cell activity, (5) restoration of BBB integrity by downregulating the matrix metalloproteinases, and (6) repression of nitric oxide production by myeloid cells. Intravenous methylprednisolone could improve visual acuity and preserve RNFL thickness. Another option therapy for acute attack of NMOSD are plasma exchange (PLEX) for patient who shows suboptimal improvement with IVMP and intravenous immunoglobulins (IVIg) therapy for patient with contraindication for IVMP injection or additional therapy for IVMP. Kleiter et al reported, NMOSD attack in 181 patients, only 17% achieved complete remission and 16.2% had no improvement after receiving IVMP as the first treatment.9,12-14 In this study, the patient had significant visual improvement from 1/300 on RE and no light perception on LE to 0.16 on both eyes on the 3rd weeks follow up after methylprednisolone administration.
IV. CONCLUSION
Optic neuritis in NMOSD may occur after COVID-19 infection. Post- infectious immune-mediated etiology may be the pathogenesis in the late-onset.
During this pandemic, patients with optic neuritis need to ask about symptoms or history of COVID-19.
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