Neuro-Ophthalmic Manifestations of COVID-19
The severe acute respiratory syndrome coronavirus (SARS-CoV-2 virus) is an enveloped positive-strand RNA virus that is part of the coronaviridae family. Infection with the SARS-CoV-2 virus is known to cause coronavirus disease 2019 (COVID-19), a disease that rapidly spread starting in December 2019 after the first case was reported in Wuhan, China. The World Health Organization (WHO) declared a global pandemic in March 2020 due to the catastrophic far-reaching effects of the virus and it has since caused over 6 million confirmed fatalities. Advancements in the understanding of disease pathogenesis enabled the creation of a multitude of treatments and vaccinations. Although the COVID-19 burden has slowly decreased, many countries remain concerned due to outbreaks of new variants of the disease  .
Even though COVID-19 presentations range from being completely asymptomatic to multiorgan failure and death, the disease usually presents with fever, cough, and shortness of breath. The infection is not purely a respiratory disease and can result in coagulopathies, acute kidney injury, neurological injury, and cardiac arrest. Of importance, multiple neuro-ophthalmic presentations of COVID-19 have been described in the literature.
To date, COVID-19 has spread to over 223 countries causing over 590 million confirmed cases since it was declared a pandemic. The omicron variant remains a major concern for over 200 countries per a recent report from the WHO. The United States is the country with the highest number of reported infections and deaths caused by the disease. COVID-19-related deaths were the third most common cause of death in 2020 following heart disease and cancer. Those that were at the highest risk of severe infection were above the age of 60 and had underlying medical comorbidities .
The SARS-CoV-2 virus has multiple structural proteins, of which the spike (S) protein is of fundamental importance in disease transmission. This S protein facilitates viral entry into host cells by binding the angiotensin-converting enzyme 2 (ACE2) receptors. These receptors are abundant in the respiratory epithelium allowing for the respiratory spread of the infection. After infection, SARS-CoV-2 replication results in direct virus mediated damage followed by inflammation and over secretion of cytokines caused by immune activation of monocytes, neutrophils, and T lymphocytes. Severe COVID-19 infections might result in a cytokine storm resulting in increased local and systemic inflammation with the development of pulmonary edema with increased vascular permeability.
The respiratory system is the primary target of SARS-CoV-2. Other organs that could be impacted include the kidneys, cardiovascular system, hepatobiliary system, gastrointestinal system, and central nervous system. This is due to the presence of ACE2 receptors in a variety of organs, including the esophagus, cardiac cells, bladder urothelial cells, kidney proximal tubular cells, and the brain .
The mechanism through which SARS-CoV-2 spreads to neuronal tissue is not fully understood. The virus can access the brain by spreading to the olfactory nerves, the meninges, choroid plexus, or through hematogenous route. Abnormal immune activation could also contribute to the neuronal disturbances observed in patients with COVID-19 as pro-inflammatory cytokines can cause damage and the virus can potentially stimulate abnormal auto-antibody production . The neuro-ophthalmic presentations of COVID-19 may concur with systemic and pulmonary symptoms, or days to weeks after disease resolution .
Neuro-Ophthalmic presentations :
Multiple neuro-ophthalmic presentations in relation to COVID-19 have been reported and are listed in Table 1 below.
Table 1: Neuro-ophthalmic manifestations of COVID-19
1-Headache and ocular pain
4-Stroke related afferent disease including optic neuropathy and homonymous hemianopsia
5-Stroke related efferent disease including diplopia and ophthalmoplegia
6-Ocular motor cranial neuropathies
8-Anisocoria (tonic pupil, Horner syndrome)
9-Ptosis (Horner syndrome or third nerve palsy)
Some of the initial and most prevalent neuro-ophthalmic manifestations of COVID-19 infection include ocular pain and headache. Up to 71% of those positive for SARS-CoV-2 have reported headaches, and 34% have reported ocular pain. The mechanism of developing headaches and ocular pain in COVID-19 infection is not clear, but it postulated that activation of the trigeminal neve by vasculopathy or viral insult, hypoxia, or increased inflammatory cytokines are responsible for these symptoms .
Several cases of optic neuritis have been described following infection with SARS-CoV-2. One case of optic neuritis was described in the recovery phase of the infection. Other cases noted positive myelin oligodendrocyte glycoprotein (MOG) antibody with confirmed COVID-19 infections. It was presumed that the infection triggered the production of autoimmune antibodies  . There have been reported cases of cerebrovascular ischemia caused by COVID-19 infection with infarction of the optic nerve after occlusion of the internal carotid artery, central retinal artery, and ophthalmic artery. Papillophlebitis has also been reported following COVID-19 infection .
COVID-19 has been linked to damage to the third, fourth, sixth, and seventh cranial nerves. These manifestations can arise on their own or in conjunction with other disorders such as Miller Fisher syndrome, myasthenia gravis, and elevated intracranial pressure .
Symptoms of ocular motor abnormalities such as ptosis and diplopia have been reported in COVID-19 individuals from the onset of typical symptoms to days later . A COVID-19-related abducens nerve palsy was described in a case report . After COVID-19 infection, Miller Fisher syndrome with paresthesia and hyporeflexia was observed . A case study also described the onset of myasthenia gravis in patients with positive cholinergic receptor antibodies. It was thought that the virus caused an autoimmune reaction in those who were predisposed to it . Furthermore, incidences of unilateral and bilateral trochlear nerve palsy have been recorded in the context of COVID-19 infection .
COVID-19 infection can result in a pro-inflammatory and hypercoagulable condition, which can lead to disorientation, increased intracranial pressure, papilledema, and a false localizing sixth nerve palsy after cerebral venous sinus thrombosis . Children infected with COVID-19 can develop a multisystem inflammatory disease, which can lead to pseudotumor cerebri .
Infection with COVID-19 increases stroke risk which can cause visual defects if the posterior circulation and occipital lobe are affected . Additionally, there are several cases linking COVID-19 infection with posterior reversible vasoconstriction syndrome (PRES), which can cause patients to develop visual field defects . Hallucinatory palinopsia can also occur in patients with PRES and COVID-19 .
Nystagmus has been described with COVID-19 associated benign paroxysmal positional vertigo, acute labyrinthitis, and encephalitis. COVID-19 pneumonia involving the upper part of the lung has also been reported to cause Horner’s syndrome . Following severe systemic COVID-19 infection, immune-mediated encephalitis can also result in oscillopsia with ataxia and myoclonus  or opsoclonus myoclonus ataxia syndrome .
Unilateral or bilateral tonic (Adie) pupil can occur from days to a month following the initial COVID-19 infection. Tonic (Adie) pupil associated with COVID-19 infection has also co-occurred with inflammatory multifocal choroiditis and trochlear nerve palsy. This presentation is thought to be a result of immune-mediated injury and not direct viral neuronal injury .
It has been noted that COVID-19 infection increases the risk of secondary rhino-orbital-cerebral mucormycosis (ROCM) as the incidence of ROCM increased to epidemic levels during the second COVID-19 wave in India. It is important to note that most of the patients that developed ROCM received corticosteroids prior to the fungal infection (87%), and the second most notable risk factor was diabetes mellitus (78%) .
COVID-19 vaccine complications:
Several neuro-ophthalmic complications were reported after COVID-19 vaccination. These complications occurred with different types of vaccines and are intracranial hemorrhage, cerebral venous thrombosis, post-vaccination cranial neuropathy, pupillary abnormalities such as Horner’s syndrome, Holmes-Adie pupil, miosis, mydriasis, bilateral arteritic anterior ischemic optic neuropathy, acute ischemic stroke, optic neuritis, and benign paroxysmal positional vertigo .
“Long COVID” describes the effects of the disease that persist for weeks to months after the initial infection. Neuro-ophthalmic symptoms of long COVID include headaches, optic neuritis, corneal nerve damage, eye movement alterations, papillophlebitis, and inflammatory retinal vascular occlusion. Chronic inflammation and increased cytokine production seem to be the pathophysiological mechanisms of the neuro-ophthalmic presentations of long-COVID .
The gold standard to detect COVID-19 during the first week of the infection is through DNA amplification by polymerase chain reaction (PCR) to identify virus presence in an individual’s respiratory epithelium. Nasopharyngeal swabs are used to collect patient samples. Such tests identify different regions of the virus’s genome and multiple kits are commercially available. This test’s sensitivity is not ideal, and therefore diagnosis should also be guided by clinical data and epidemiological history. Serological tests that detect the humoral response against SARS-CoV-2 are recommended from the second week of infection and onwards. These tests detect antibodies directed against virus proteins .
Patients who present with acute fever and respiratory symptoms and specific neurologic complaints such as diplopia, changes in visual acuity, pain with eye movement, and changes in color vision should be tested for COVID-19. Clinicians should look for any signs of optic disc swelling, ptosis, extraocular motility defects, and pupillary abnormalities, in those patients. If hyporeflexia is noted, the miller fisher variant of Guillain barre syndrome should be considered. The optic nerves, optic nerve sheaths, and perineural region should be examined by neuroimaging to identify any possible abnormal enhancement associated with optic neuritis .
Since the beginning of the pandemic when COVID-19 understanding was limited, significant progress in disease management has been made with the rapid development of vaccines and therapeutics. The therapeutic options currently available include anti-SARS-CoV-2 monoclonal antibodies, antiviral drugs, immunomodulator agents, and corticosteroids. The clinical utility is specific and depends on disease severity and the patient’s risk factors.
Respiratory insufficiency is a common occurrence in severe COVID-19 cases. Such cases should be closely monitored with continuous pulse oximetry and supplemental oxygen should be provided to maintain an oxygen saturation of 92 to 96% .
The neuro-ophthalmic presentations of COVID-19 are usually caused by either inflammation, ischemia, hypercoagulability, or systemic abnormalities such as severe hypertension or hypoxia. There are no current standard screening or prove effective decision-making algorithms for COVID-19 related neuro-ophthalmic disease. Immunosuppressive medication can be used to manage such conditions, but their use should be carefully monitored in active cases as they can increase the risk of infection complications . Relating to neurological damage from stroke-associated COVID-19, therapeutic anticoagulation can be used to decrease risk, and IV thrombolytics and mechanical thrombectomy can be used for the treatment of acute ischemic stroke .
Understanding COVID-19 is continuing to evolve. Even though the respiratory aspects of the disease are most often discussed, the infection can affect multiple different body systems, with multiple neuro-ophthalmic presentations being described in the literature. In patients with unexplained neurologic manifestations post-COVID-19 infection, clinicians may consider applying the Bradford Hill causality criteria to estimate the strength of association. The treatment regimen should be individualized in each case and should be generally used to manage increased risk of ischemia, inflammation, and hypercoagulability.
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