Fifteen acute retrobulbar optic neuritis associated with COVID-19: A case report and review of literature

Abstract

BACKGROUND

A subtype of the Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is suggested to be responsible for the outbreak in Northern China since the quarantine was lifted in December 2022. The coronavirus disease 2019 virus is primarily responsible for the development of respiratory illnesses, however, it can present a plethora of symptoms affecting a myriad of body organs. This virus has been theorized to be linked to demyelinating lesions of the peripheral and central nervous system including transverse myelitis and acute retrobulbar optic neuritis (ARON). For example, magnetic resonance imaging (MRI) of the orbit and brain showed enlargement of the retrobulbar intraorbital segments of the optic nerve with high T2 signal, and no abnormalities were seen in the brain tissue. In this case series, we analyzed the connection between SARS-CoV-2 infection and the onset of ARON.

CASE SUMMARY

Fifteen patients, and a teenage boy who did not have any pre-existing ocular or demyelinating diseases suddenly experienced a loss of vision after SARS-CoV-2 infection. The patients expressed a central scotoma and a fever as the primary concern. The results of the fundus photography were found to be normal. However, the automated perimetry and MRI scans showed evidence of some typical signs. Out of the 15 patients diagnosed with ARON after SARS-CoV-2 infection, only one individual tested positive for the aquaporin-4 antibody.

CONCLUSION

Direct viral invasion of the central nervous system and an immune-related process are the two primary causes of SARS-CoV-2-related ARON.

Key Words: SARS-CoV-2, COVID-19, Acute retrobulbar optic neuritis, Central scotoma, Case report

Core Tip: Our study is the first to elucidate the relationship between the Omicron variant of severe acute respiratory syndrome coronavirus 2 and acute retrobulbar optic neuritis in China, which may be attributed to two main factors: Immune involvement in the process and direct viral infiltration of the central nervous system. In addition, hypoxia and ischemia may be associated with the appearance of this disease. Further investigation is needed to gain a more complete picture of this relationship.

INTRODUCTION

Recent reports have suggested that the primary pathogen responsible for the outbreak in Northern China since quarantine was lifted in December 2022 is a subtype of the Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)[1]. It is theorized that this virus may be linked to certain demyelinating conditions of the peripheral and central nervous systems (CNS), including multiple sclerosis, acute demyelinating encephalomyelitis (ADEM), transverse myelitis (TM), neuromyelitis optica spectrum disorder[2-4] and acute retrobulbar optic neuritis (ARON)[5,6]. It is still unclear, though, how coronavirus disease 2019 (COVID-19) and symptoms of neurological disorders are related. It is undetermined if this is because of the neurotropic properties of the virus or an immune-related reaction[7].

Neurological complications from the COVID-19 infection have been noted to be similar to those from previous coronavirus infections, like SARS in 2003 and MERS in 2012. These symptoms include encephalopathy, encephalitis, hemorrhagic and ischemic stroke, sepsis, vasculitis, and Guillain-Barre syndrome[8-10]. According to a study conducted by Mao et al[11], out of the 214 COVID-19 patients, 78 of them experienced neurological symptoms after 4 wk. Those who experienced these symptoms were typically older, more seriously ill, and had other underlying medical issues. Although rare, there are cases where the virus manifests as a neurological disorder[12].

Magnetic resonance imaging (MRI) results of 22 patients revealed evidence of ischemic stroke, meningeal enhancement, and alterations in perfusion. Nevertheless, investigation of the cerebrospinal fluid (CSF) did not indicate the presence of the SARS-CoV-2 virus[13]. Additionally, the Strasbourg group reported 64 consecutive patients with confusion (65%), agitation (69%), and the presence of signs pointing to corticospinal tract (67%). Moreover, there are a few isolated case reports on myoclonus and demyelination in some literature[14-16].

Ocular issues associated with COVID-19 include alterations to the eyelids, anterior segment, ocular surface, and posterior segment[17]. It is hypothesized that the virus' neurotropism may be the cause of neuroophthalmic symptoms[18], and molecular mimicry may also be responsible, with viral antigens stimulating the host's immune system to target myelin proteins in the CNS[19-21]. Three of the cases discussed in this paper experienced mild viral symptoms and their tests came back positive for COVID-19. They did not require oxygen or steroids for COVID-19 infection. However, despite their recovery, the patients continued to experience visual loss, suggesting that the cause, as suggested by their response to steroids, was a viral-induced inflammatory disorder.

It has been suggested that approximately 36% of COVID-19 cases have demonstrated neurological manifestations, including headaches, loss of smell, dizziness, reduced taste, and ischemic stroke[19]. Ischemic stroke, although primarily observed in the elderly, may also affect younger people of a comparable age to those presenting with neuro-ophthalmic characteristics[20]. Animal studies have indicated a potential relationship between optic neuritis and COVID-19, implying that the virus may possess a neuro-tropic nature, which could explain the neuro-ophthalmic and neurological side effects[5]. COVID-19 ocular symptoms can appear at any stage of the illness, with an average 5-d interval between the onset of the illness and diagnosis of neuro-ophthalmic symptoms. Observing ocular surface and anterior segment manifestations takes around 8.5 d, whereas observing posterior segment and orbital pathologies takes about 12 d [17].

It has been discovered that some patients developed optic neuritis a few days after contracting COVID-19. The symptoms included visual loss, impairments to the visual field, relative afferent pupillary defect (RAPD) in the eyes with the most severe symptoms, and augmentation of the optic nerve as revealed by an MRI. The outcomes of the two cases demonstrated the existence of anti-myelin oligodendrocyte glycoprotein (MOG) antibodies. Other investigations, including an MRI scan, CSF analysis, viral panel, and immunological profile, did not identify any other causes. After the standard regimen of intravenous methylprednisolone and oral prednisolone, optic neuritis was treated, resulting in the restoration of vision and the disappearance of disc edema. After the COVID-19 infection, viral prodrome occurs before the development of parainfectious demyelinating disease known as MOG antibody-associated optic neuritis[21]. Furthermore, the CSF results did not reveal the presence of the virus, indicating that the immune system may be culpable for this occurrence rather than the virus itself. It is plausible that viral infection may lead to a rise in demyelinating neurological conditions in the future[19].

CASE PRESENTATION

Chief complaints

A teenage boy experienced a sudden vision loss in both eyes accompanied by oculomotor pain.

History of present illness

The teenage boy presented to our ophthalmic Outpatient Department on December 4, 2022, with sudden vision loss in both eyes accompanied by oculomotor pain. He had experienced a fever the day prior and a positive pharyngeal swab reverse transcription-polymerase chain reaction (RT-PCR). He presented with central scotoma accompanied by other symptoms, including fever, sore throat, gastrointestinal distress, and headache. He took ibuprofen or other proprietary Chinese medicines at home to alleviate his symptoms.

History of past illness

The teenage boy's medical history was devoid of any conditions.

Personal and family history

The teenage boy reported no family history of any disease.

Physical examination

Visual acuity was assessed in both eyes at a distance of 20 centimeters from the face. To assess color perception, red and green filters from the trial set were subjected to torchlight, which was determined to be faulty. Full extraocular muscle movements were present in the lateral gaze, though he was uncomfortable, and bilaterally, RAPD was observed. Upon evaluation of the orbit, eyelids, lacrimal system, and anterior and posterior segments, no abnormalities were found. The Topcon non-contact tonometer showed an intraocular pressure of 14 mmHg in the right eye and 13 mmHg in the left eye.

Laboratory examinations

Results of blood inflammatory markers assessments, including D-dimer, C-reactive protein, lactate dehydrogenase, procalcitonin, and erythrocyte sedimentation rate, were within the normal range. Screening for autoimmune optic neuritis, including anti-MOG antibodies, anti-myelin basic protein antibody, and aquaporin-4 antibodies, was unremarkable.

Imaging examinations

Imaging tests revealed central blindness in both eyes (Figure 1), the fundoscopy examination findings were normal (Figure 2), while there was an enlargement of both optic nerves located behind the eyes, with a high T2 signal. No irregularities were observed in the brain tissue (Figure 3).

Figure 1  Central scotoma was shown in the perimetry of both eyes (black arrow).

Figure 2  Images of bilateral normal fundus.

Figure 3  The orbital and brain magnetic resonance imaging results indicated an enlargement of the retrobulbar intraorbital segments of the optic nerve, which had a high T2 signal (yellow double arrow), and the brain tissue was in a healthy state.

FINAL DIAGNOSIS

The teenage boy was diagnosed with ARON based on his symptoms and imaging features.

TREATMENT

The teenage boy was given intravenous immunoglobulins (IVIg) and methylprednisolone (1000 mg qd) based on body weight. The dose of methylprednisolone was reduced every 3 d until it reached 120 mg, then switched from IVIg to oral steroids (initial dose: 50 mg prednisone acetate).

OUTCOME AND FOLLOW-UP

After treatment, the teenage boy’s vision recovered to normal condition and his visual field returned to its initial level. He was discharged and consulted our physician every week. The dose of prednisone acetate was reduced by 5 mg per week to 0 mg and the recurrence of ARON was not observed for each visit.

The cases with cerebellar infection were treated with IVIg and methylprednisolone (7.5-30 mg/Kg qd). After receiving IVIg for 3 d to 5 d, most of the patients recovered from their initial condition, while the others continued receiving IVIg because they did not show any significant improvement. Following a switch from IVIg to oral steroids, two of the fifteen patients who were diagnosed with ARON associated with COVID-19 recovered to their normal status, and the remaining 13 patients improved. The relevant data, ocular examinations, and blood tests of the patients are outlined in Tables 1-3. Data that does not conform to the normal distribution is represented as M (P25, P75). This study was approved by the Medical Ethics Committee of Hebei Eye Hospital. Before beginning the study, all enrolled patients gave their informed consent to participate, according to the Declaration of Helsinki.

Table 1 Basic features.

Sex as M/F	Age in yr, M(P25, P75)	Time relation between fever and ARON in d, M(P25, P75)	Comorbidities	Unilateral/bilateral
6/9	27(18, 39)	4(2, 6)	None	8/7

M: Male; F: Female.

Table 2 Summary of the ocular examination results for all patients.

Vision	Color defect	IOP	Oculomotor pain (+)/(-)	RAPD (+)/(-)	Orbit, eyelid, lacrimal system	Conjunctiva, corneal, anterior chamber, iris	Lens, vitreous	Retina, optic nerve papilla
CF (10)/HM (5)	Achromatism in red and green (6)/indistinguishable in red and green (9)	Normal	10/5	15/0	Normal	Normal	Normal	Normal

CF: Counting finger; HM: Hand moving; IOP: Intraocular pressure; RAPD: Relative afferent pupillary defect.

Table 3 Summary of the blood test results for all patients.

C-reactive protein (+)/(-)	Procalcitonin (+)/(-)	D-dimer (+)/(-)	Lactate dehydrogenase (+)/(-)	ESR (+)/(-)	MOG (+)/(-)	AQP-4 (+)/(-)	MBP (+)/(-)
0/15	0/15	0/15	0/15	3/12	0/15	1/14	0/15

AQP-4: Aquaporin 4 antibody; ESR: Erythrocyte sedimentation rate; MBP: Myelin basic protein; MOG: Myelin oligodendrocyte glycoprotein.

DISCUSSION

Reports indicate that the occurrence of ocular symptoms in COVID-19-infected individuals may range from 2%-32%[22]. However, the precise causal association between SARS-CoV-2 infection and these ocular symptoms has yet to be evaluated with certainty. The rest of these patients showed notable therapeutic improvement. Although the exact pathological mechanism by which the virus contributes to the disease is still unknown, there are two possible theories: either the virus causes direct harm to blood vessels, neurons, and other tissues, or the immune system response to the virus eventually causes damage[23-26]. To answer these questions, more comprehensive studies that utilize standardized approaches on a larger population scale are required.

The first hypothesis proposes that SARS-CoV-2 may directly impact the CNS and cause neurological harm. It is still unknown how the virus enters the CNS. Nevertheless, other theories regarding how SARS-CoV-2 infection propagated include hematogenous transmission from the circulatory system to the CNS or trans-neuronal transmission via the olfactory pathway[27]. Furthermore, studies have demonstrated that the virus can cross the blood-brain barrier (BBB)[28]. Because the virus's components resemble the CNS's proteins, lipids, or carbohydrates, in certain instances, the T cell and/or antibody response to the virus may target a CNS cell or component. Molecular mimicry is the term currently used to describe this phenomenon, which was previously known as cross-reactivity. An excessively active immune system that lasts a long time can be harmful because it can cause tissue damage, while a strong immunological response is essential for adaptive immunity[29]. Within the first 2 wk of the infection, COVID-19 patients are more likely to have respiratory distress and death due to a phenomenon known as a "cytokine storm", which has been related to an overabundance of immune response and multi-organ failure[30,31].

Research has indicated that SARS-Cov-2 is neurotropic and neuro-invasive, directly causing damage to the nervous system. This is a result of the virus's capacity to attach to ACE-2 receptors in the CNS or pass through Virchow Robin spaces, allowing it to enter the bloodstream[32].

It has been proposed that direct viral infiltration of the CNS can cause acute or delayed demyelination of the CNS[33]. Moreover, the ischemia-hypoxia caused by the infection may further aggravate this effect. Additionally, delayed CNS damage is thought to be the result of an inappropriate immune reaction that follows the initial infection, which leads to CNS demyelination.

The second hypothesis is related to an immune-mediated process[34]. It has been shown that pro-inflammatory cytokines, such as tumor necrosis factor-α and interleukin-1β, can cross the BBB and affect the main immune cells in the CNS, such as macrophages, microglia, and astrocytes. Hence treatment with steroids could be the reason behind the improvement, as steroids can penetrate the BBB and promote remyelination[35]. Our findings showed that a positive result from a nasopharyngeal RT-PCR test was the only means to detect CNS inflammation associated with COVID-19. Two ADEM cases simultaneously tested positive for SARS-CoV-2 using the CSF RT-PCR[36,37]. Furthermore, a serum test for SARS-CoV-2 IgG and IgM antibodies revealed positive results in the case of TM[38]. Whether a direct invasion of the virus causes CNS disorders is still uncertain. An increase in CSF protein was found in eleven cases of TM, including five cases of ADEM, four cases of acute hemorrhagic necrotizing encephalitis/acute hemorrhagic leukoencephalitis, and one case of myelitis. These findings suggest a possible neuroinflammatory process along with alterations to the blood-meningeal barriers or BBB.

It has been suggested that the emergence of antibodies directed against myelin, a consequence of the virus, may be an additional cause of Guillain-Barre syndrome after SARS-CoV-2 infection. Numerous reports have indicated a para- and post-infectious source, which is associated with a heightened innate immunity and an irregularity in the immune system[34].

Our study was the first to elucidate the association between the Omicron variants of SARS-CoV-2 and ARON in mainland China. Nevertheless, there are certain limitations to this research. Many older patients with visual loss were prioritized for treatment in other medical facilities due to the seriousness of respiratory system issues, which prevented us from gathering their data. Given the constraints of its duration and sample size, this study warrants additional research to fully understand the association between COVID-19 and ARON. Additionally, we will explore in depth the relationship between other variants such as Alpha, Delta variants and ARON in future studies.

CONCLUSION

We report that SARS-CoV-2-related acute bilateral retrobulbar optic neuritis may be attributed to two main factors: Immune-involved process and direct viral infiltration of the CNS. In addition, hypoxia and ischemia may be implicated in the emergence of the condition. Further investigation is required to gain a more comprehensive comprehension of the relationship.