Neuro-ophthalmic signs of COVID-19 refer to a variety of clinical manifestations resulting from damage to the neuro-ophthalmic system, including the optic nerve, cranial nerves, visual pathways, and pupillary pathways, associated with SARS-CoV-2 infection (COVID-19).
SARS-CoV-2 was first reported in Wuhan, China in 2019, and the WHO declared a pandemic in March 2020. It has since spread to over 223 countries, causing more than 770 million confirmed cases and approximately 7 million deaths (WHO). In 2020, it became the third leading cause of death in the United States after heart disease and cancer. Neurological complications have been reported in about 4% of severe COVID-19 patients 1), with the highest risk of severe illness in individuals aged 60 and older with underlying medical conditions.
Neurological complications have been reported in about 4% of severe COVID-19 cases 1). Headache occurs in up to 71% of SARS-CoV-2-positive individuals, and eye pain in 34%. Neuro-ophthalmic signs such as optic neuritis and cranial nerve palsy may appear during or after infection.
Neuro-ophthalmic signs associated with COVID-19 are diverse. The main categories are shown below.
Optic Nerve System
Optic neuritis: Unilateral or bilateral. May be associated with neuromyelitis optica spectrum disorders and MOG-related diseases.
Optic nerve infarction: Caused by internal carotid artery occlusion. DWI shows optic nerve ischemia.
Optic disc phlebitis: Decreased visual field sensitivity, retinal vascular dilation and tortuosity, papilledema, retinal hemorrhage.
Optic neuroretinitis: Acute unilateral vision loss, optic disc swelling, and perifoveal star-shaped hard exudates.
Cranial Nerves and Ocular Motor System
Cranial nerve palsy: Single or multiple involvement of cranial nerves III, IV, VI, and VII. Occurs in the context of Fisher syndrome, Guillain-Barré syndrome, and myasthenia gravis.
Nystagmus and ocular motor disorders: Associated with BPPV, acute labyrinthitis, rhombencephalitis, and Bickerstaff brainstem encephalitis. Opsoclonus-myoclonus-ataxia syndrome (OMAS) has also been reported.
Pupillary abnormalities: Adie tonic pupil (days to 1 month after infection), Horner syndrome (associated with pneumonia affecting the upper lung).
Visual pathway and other
Visual pathway disorders: Homonymous hemianopia due to stroke, cortical blindness, reading difficulty. Transient cortical visual loss and hallucinatory palinopsia due to PRES (posterior reversible encephalopathy syndrome).
Idiopathic intracranial hypertension (IIH): Frequently reported in children due to MIS-C.
Secondary infection (ROCM): Rhino-orbital-cerebral mucormycosis. 87% have a history of steroid use, 78% have diabetes.
Double vision after COVID-19 is mainly caused by cranial nerve III, IV, and VI palsy. It can also occur in the context of Fisher syndrome (characterized by the triad of ophthalmoplegia, ataxia, and areflexia), Guillain-Barré syndrome, and myasthenia gravis. Cases associated with cerebral venous sinus thrombosis (CVST) have also been reported.
SARS-CoV-2 is an enveloped, positive-sense single-stranded RNA virus belonging to the family Coronaviridae. The spike (S) protein binds to the ACE2 receptor to enter host cells. ACE2 receptors are expressed not only in respiratory epithelium but also in neurons and glial cells of the brain.
The following routes of entry into neural tissue have been proposed:
SARS-CoV-2 infection has been reported as a risk factor for non-arteritic anterior ischemic optic neuropathy (NA-AION). 2) The proposed mechanism is inflammatory/autoimmune thrombotic microangiopathy. NA-AION has also been reported after COVID-19 vaccination. 2)
After vaccination, optic neuritis, bilateral AION, cerebral venous thrombosis, pupillary abnormalities (Horner syndrome, Holmes-Adie pupil), acute ischemic stroke, BPPV, and others have been reported. Acute macular neuroretinopathy (AMN) has also been suggested to be directly associated with vaccination or infection.
The diagnostic methods for COVID-19 are shown below.
| Test method | Characteristics | Timing of application |
|---|---|---|
| PCR (nasopharyngeal swab) | Gold standard | First week of infection |
| Serological test | Detection of antibodies against viral antigens | From the second week of infection onwards |
Sensitivity is not perfect; diagnosis is made in combination with clinical data and epidemiological history.
The following findings are confirmed during examination.
In the differential diagnosis of optic neuritis, ischemic, compressive, neoplastic, sinus-related, toxic, and hereditary optic neuropathies must be excluded. Features of atypical optic neuritis include the following.
Evaluation of anti-AQP4 and anti-MOG antibodies is also important for differential diagnosis. For differentiation from NA-AION, refer to age, presence of pain, visual field pattern, and VEP findings. 2)
Systemic management of COVID-19 includes anti-SARS-CoV-2 monoclonal antibodies, antiviral drugs, immunomodulators, and corticosteroids. For respiratory failure, monitoring with pulse oximetry and maintaining oxygen saturation at 92–96% is fundamental.
Dexamethasone or remdesivir has been reported to be associated with a reduced frequency of neurological complications including stroke, seizures, and meningitis. Combination of both drugs shows a synergistic effect, and dexamethasone also reduced the risk of neurological complications in non-hypoxic COVID-19. 1)
Treatment of optic neuritis is as follows.
| Disease type | First-line treatment | Notes |
|---|---|---|
| Typical optic neuritis | Steroid pulse therapy | Accelerates visual recovery (limited impact on final visual acuity) |
| Atypical optic neuritis | Steroid pulse therapy | Mandatory indication. If NMO or collagen disease is suspected, collaborate with specialists |
Management is based on addressing inflammation, ischemia, hypercoagulable states, and systemic abnormalities (hypertension, hypoxia). For stroke-related cases, therapeutic anticoagulation, intravenous thrombolysis, and mechanical thrombectomy are options. Immunosuppressive drugs should be used with caution in active infections due to the risk of infectious complications. Currently, there are no standard screening protocols or established decision-making algorithms.
The basic treatment for optic neuritis is steroid pulse therapy (methylprednisolone 1,000 mg/day intravenously for 3 days). This treatment is mandatory for atypical optic neuritis (bilateral, steroid-dependent, systemic complications, etc.). If NMO spectrum disorder or collagen disease is suspected, collaboration with a neurologist is necessary.
The spike (S) protein of SARS-CoV-2 binds to the ACE2 receptor to enter host cells. ACE2 receptors are widely distributed in respiratory epithelium, esophagus, cardiomyocytes, bladder urothelium, renal proximal tubules, and the brain (neurons and glial cells).
The following pathways are thought to be involved in the pathogenesis of neuro-ophthalmic signs.
Neuro-ophthalmologic signs appear simultaneously with systemic symptoms or within a few days to weeks.
The presumed mechanism of NA-AION is inflammatory/autoimmune thrombotic microangiopathy due to SARS-CoV-2 infection. 2)In vaccine-related neuro-ophthalmologic complications, acute macular neuroretinopathy (AMN) due to microvascular ischemia of the choriocapillaris has been reported.
Neuro-ophthalmologic symptoms in long COVID are presumed to be maintained by chronic inflammation and persistently increased cytokine production.
Grundmann et al. (2022) reported in an analysis of patients with severe COVID-19 that treatment with dexamethasone or remdesivir was associated with a reduced frequency of neurological complications including stroke, seizures, and meningitis 1). Combination of both drugs showed a synergistic effect, and dexamethasone also reduced the risk of neurological complications in non-hypoxic COVID-19. Further investigation is needed to determine the role of these drugs in preventing neurological complications.
Neuro-ophthalmic complications have been reported after COVID-19 vaccination.
In long COVID, where neuro-ophthalmic symptoms persist after recovery from COVID-19, the following have been reported.
Associations between both COVID-19 infection and vaccination with giant cell arteritis (GCA) have been reported, and further accumulation of evidence is expected.
