Ophthalmic Manifestations Of Coronavirus (COVID-19)

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Continuing Education Activity

Several reports of suspected ocular manifestations of coronavirus disease 2019 (COVID-19) have prompted investigations into ocular signs, symptoms, and transmission. This activity reviews the evaluation and management of ocular manifestations of COVID-19 and highlights the interprofessional team's role in managing patients with this condition.

Objectives:

  • Summarize the epidemiology of ocular manifestations of COVID-19.
  • Describe the typical presentation of a patient with ocular manifestations of COVID-19.
  • Outline management considerations for patients with ocular manifestations of COVID-19, including key patient counseling on disease transmission prevention.
  • Explain the importance of collaboration and communication among the interprofessional team to improve outcomes for patients affected by COVID-19.

Introduction

Since December 2019, coronavirus disease 2019 (COVID-19) has become a global pandemic caused by the highly transmissible severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).[1] Initially, there were several reports of eye redness and irritation in COVID-19 patients, both anecdotal and published, supporting conjunctivitis as an ocular manifestation of SARS-CoV-2 infection. Reports continue to emerge on further associations of COVID-19 with uveitic, retinovascular, and neuro-ophthalmic disease.

During the 2003 severe acute respiratory syndrome (SARS) outbreak, a study detected SARS-CoV in tear samples in SARS patients in Singapore.[2] Lack of eye protection was a primary risk factor of SARS-CoV transmission from SARS patients to healthcare workers in Toronto, prompting a concern that respiratory illness could be transmitted through ocular secretions.[3][4] Similar concerns have been raised with SARS-CoV-2, especially among eye care providers and those on the front lines triaging what could be initial symptoms of COVID-19.

As conjunctivitis is a common eye condition, ophthalmologists may be the first medical professionals to evaluate a patient with COVID-19. Indeed, one of the first providers to voice concerns regarding the spread of coronavirus in Chinese patients was Dr. Li Wenliang, MD, an ophthalmologist. He later died from COVID-19 and was believed to have contracted the virus from an asymptomatic glaucoma patient in his clinic.[5]

The authors of this article have attempted to collect the most up-to-date information on ophthalmic manifestations of COVID-19 as a resource for identifying symptoms, providing diagnostic pearls, and mitigating transmission.

Etiology

SARS-CoV-2 is a novel enveloped, positive single-stranded RNA beta coronavirus that causes COVID-19, originally linked to an outbreak in Wuhan of China's Hubei province.[1] Direct contact with mucous membranes, including the eye, is a suspected route of transmission.

Coronaviruses can cause severe ocular disease in animals, including anterior uveitis, retinitis, vasculitis, and optic neuritis in feline and murine species. However, ocular manifestations in humans are typically mild and rare,[6] although there are increasing numbers of associated ocular findings in patients positive for the COVID-19. There are no described ocular manifestations of Middle East respiratory syndrome (MERS) or SARS, though, as previously stated, SARS-CoV was isolated in ocular secretions.[2] Other coronaviruses have been found to cause viral conjunctivitis in humans.[7]

Epidemiology

At the time of writing the initial article on April 4, 2020, there were 1,272,953 confirmed cases and 69,428 deaths due to COVID-19 worldwide, according to the World Health Organization (WHO), with 79,332 new cases confirmed in the previous 24 hours. At the time, the Center for Disease Control and Prevention (CDC) had reported 337,278 cases and 9,637 deaths in the United States to that date. On April 16, 2021, just over a year since our initial review, the number of deaths worldwide has crossed the 3 million mark. The severity of the pandemic is emphasized by noting the rate of deaths: it took 8.5 months after the first fatality in China to mark the loss of the first 1 million lives, 3.5 months to reach 2 million, and 3 months for the loss to cross 3 million lives. 

As of December 23, 2021, there have been 51,574,787 confirmed cases of COVID-19 and 809,300 deaths in the United States. Globally, there have been over 276 million confirmed cases of COVID-19 and 5,374,744 deaths reported to the WHO. As of December 23, 2021, a total of 8,649,057,088 vaccine doses have been administered worldwide. The United States has had the most infections to date, followed by India, Brazil, the United Kingdom, Russia, Turkey, and France.

Viral mutations leading to variants of SARS-CoV-2 have been found around the world: the B.1.1.7 in the United Kingdom in early 2020, the B.1.526 in the United States in November 2020, the B.1.525 in the United Kingdom and Nigeria in December 2020, and the B.1.351 in South Africa in late 2020. The Delta variant B.1.617.2 was initially identified in India in December 2020 and rapidly spread through over 60 countries due to a 40-60% increase in transmissibility, becoming the dominant strain globally by August 2021.[8] Most recently, the Omicron variant B.1.1.529 was named a variant of concern in late November 2021 after cases emerged out of Botswana and South Africa with rapid, exponential spread.[9]

Early studies postulated that ocular manifestations of COVID-19 were rare overall. Only 9 (0.8%) out of 1,099 patients from 552 hospitals across 30 provinces in China were reported to have "conjunctival congestion" from December 2019 through January 2020.[10] More recent data, however, have supported a much higher incidence of ocular signs and symptoms. A 2021 meta-analysis by Nasiri et al. reported a pooled prevalence of all ocular manifestations among 7,300 COVID-19 patients as 11.03%, with the most frequent ocular disease being conjunctivitis (88.8%).[11] In the same meta-analysis, dry eye or foreign body sensation (16%), eye redness (13.3%), tearing (12.8%), and itching (12.6%) were among the most frequent symptoms reported. 

A case series reported ocular symptoms in 12 (31.6%) of 38 hospitalized patients with COVID-19 in Hubei province, China.[12] These 12 of 38 patients had conjunctival hyperemia (3 patients), chemosis (7 patients), epiphora (7 patients), or increased secretions (7 patients). Of note is that one patient who had epiphora presented with epiphora as the first symptom of COVID-19. Of those with ocular manifestations, 2 (16.7%) patients had positive results of SARS-CoV-2 on reverse-transcriptase polymerase chain reaction (RT-PCR) by a conjunctival swab, as well as by nasopharyngeal swabs. Only one patient in this study presented with conjunctivitis as the first symptom.[12] The authors noted that patients with ocular symptoms had higher white blood cell and neutrophil counts, C-reactive protein, and higher levels of procalcitonin and lactate dehydrogenase compared to patients without ocular abnormalities. 

Out of 30 hospitalized patients with COVID-19 tested by Xia et al., one patient had conjunctivitis and was also the sole patient in the study to test positive for SARS-CoV-2 in ocular secretions by a conjunctival swab. This patient did not have a severe fever or respiratory symptoms at the time of testing.[13]

Pathophysiology

The pathogenesis and tissue tropism of SARS-CoV-2 relates to the binding of the viral spike protein to its cognate receptor on human host cells— the angiotensin-converting enzyme 2 (ACE-2) receptor. Efficient cell entry requires cleavage by protein transmembrane serine protease 2 (TMPRSS2). ACE-2 is expressed primarily on respiratory mucosal and alveolar epithelial cells and has been identified in other tissues, including the gastrointestinal tract, kidney, vascular endothelial cells, immune cells, and even neurons. Virulence is achieved via direct cellular invasion and death and the induction of widespread cytokine-driven inflammation and vascular leakage.[14] Immune cell and complement debris can also lead to an increased thromboembolic state.

The potential of infection through ocular secretions is currently unknown, and it remains unclear how SARS-CoV-2 accumulates in ocular secretions. Possible theories include direct inoculation of the ocular tissues from respiratory droplets or aerosolized viral particles, migration from the nasopharynx via the nasolacrimal duct, or even hematogenous spread through the lacrimal gland.[6]

Data surrounding the expression of ACE-2 and TMPRSS2 on the ocular surface are mixed. One study demonstrated the expression of both these proteins on the cornea and limbus but observed low levels on the conjunctiva.[15] Lange et al. also found the human conjunctival to have low levels of ACE-2.[16]

A case report from Rome, Italy, isolated SARS-CoV-2 by RT-PCR from conjunctival swabs in a COVID-19 patient with ocular symptoms.[17] Conjunctival swabs were collected from hospital days 3 to 27. Although conjunctivitis was clinically resolved on day 20, the patient had detectable viral SARS-CoV-2 RNA in conjunctival samples on day 21 and subsequently on day 27 after SARS-CoV-2 was negative by nasopharyngeal swab. Because SARS-CoV-2 has not been successfully cultured from human tears or conjunctival swabs, the viability and transmissibility of SARS-CoV-2 in human ocular secretions remains uncertain.[18] Limited reports suggest that tears can be both an early and late source of infection transmission, even after the patient becomes asymptomatic.[17][19]

Using RT-PCR, Azzolini et al. found SARS-CoV-2 present on the ocular surface in 52 of 91 patients with COVID-19 (57.1%).[5] They found that even when the nasopharyngeal swab was negative, the virus was detected on the ocular surface in 10 of 17 patients. It has been postulated that the viral particles in tears may be from the lacrimal gland with diffusion from a systemic load of the virus or from direct contagion from airborne droplets.[5]

History and Physical

The prevalence of ocular manifestations in patients with COVID-19 ranges from 2% to 32%.[20][21][22][23][24][11][25]

Conjunctiva

Patients infected with SARS-CoV-2 can present with acute conjunctivitis symptoms, including eye redness, ocular irritation, eye soreness, foreign body sensation, tearing, mucoid discharge, eyelid swelling, congestion and chemosis. These symptoms have more commonly affected patients with severe systemic symptoms of COVID-19, though they can rarely present as an initial manifestation of the disease.[12] Non-remitting conjunctivitis was found to be the sole manifestation of COVID-19 in five patients with confirmed SARS-CoV-2 infection on nasopharyngeal RT-PCR; these patients never developed fever, general malaise, or respiratory symptoms throughout the course of their illness.[26]

Examination findings include those consistent with mild follicular conjunctivitis, including unilateral or bilateral bulbar conjunctiva injection, follicular reaction of the palpebral conjunctiva, watery discharge, and mild eyelid edema. Bilateral chemosis alone may represent third-spacing in a critically ill patient rather than a true ocular manifestation of the virus. A case report published by Cheema et al. described the first case of keratoconjunctivitis as the presenting manifestation of COVID-19 in North America.[27] The patient’s primary symptoms included eye redness and tearing. The examination was significant for conjunctival injection, the follicular reaction of the palpebral conjunctiva, and corneal findings that developed rapidly over 3 days, including transient pseudodendritic lesions and diffuse subepithelial infiltrates with overlying epithelial defects.

Navel et al. observed a case of severe hemorrhagic conjunctivitis and pseudomembrane formation in a patient with onset 19 days after the beginning of systemic symptoms and 11 days after admission to the intensive care unit.[28]

We saw a 46-year-old male with mild respiratory symptoms and a positive nasopharyngeal test for COVID-19. Five days after the positive test, he developed a hemorrhagic bilateral conjunctivitis with pseudomembrane formation and chemosis. The left eye had been removed some years previously for melanoma. The conjunctival of the socket showed the same hemorrhagic conjunctivitis with chemosis and pseudomembrane formation. He was treated empirically with topical antibiotics and his symptoms resolved in four weeks. He did not develop any other symptoms of COVID-19.

It should be noted that in pediatric patients, COVID-19 has been strongly associated with the Kawasaki-like illness known as multisystem inflammatory syndrome in children (MIS-C). While there have been several ocular manifestations reported in this syndrome (papilledema, iritis, keratitis), the most common ocular manifestation has been conjunctivitis.[29]

Sclera/Episclera

There have been at least two reported cases of episcleritis onset in the setting of COVID-19 infection. Otaif et al. described a 29-year-old male with unilateral episcleritis as the initial presenting symptom of SARS-CoV-2 infection, and Mangana et al. observed nodular episcleritis in a 31-year-old female.[30][31]

Feizi et al. reported two cases of anterior scleritis in patients with COVID-19.[32] The first was a 67-year-old woman with necrotizing anterior scleritis which began 3 weeks after viral symptom onset. The second was a case of sectoral anterior scleritis which was highly responsive to topical and systemic steroids in a 33-year-old male; his ocular symptoms started 2 weeks after the onset of COVID-19.

Anterior Chamber

Beyond the ocular surface, acute anterior uveitis has also been reported both in isolation and in association with COVID-19 related multi-system inflammatory disease.[33][34] Sanjay et al. also reported a case of reactivated idiopathic anterior uveitis post-COVID-19 infection; this patient had remained quiescent for 13 years prior to this episode.[35]

Retina and Choroid

Posterior segment diseases have also been suspected to be associated with COVID-19 infection. These have varied between vascular, inflammatory, and neuronal etiologies. Both ACE-2 and TMPRSS2 are highly expressed in the human retina, and a recent case series of 3 patients discovered S and N COVID-19 proteins by immunofluorescence microscopy within retinal vascular endothelial cells, presumably containing viral particles.[36][37][36]

Both central retinal vein and artery occlusions have been reported in patients without classic systemic vascular risk factors. The hypothesized mechanism includes a complement-induced prothrombic and inflammatory state induced by the virus resulting in endothelial damage and microangiopathic injury. A striking example was reported by Walinjkar et al. with a central retinal vein occlusion (CRVO) in a 17-year-old female with COVID-19.[38] Yahalomi et al. presented a similar case in a previously healthy 33-year-old.[39] Several cases of central retinal artery occlusions (CRAO) have been reported, potentially related to viral-induced endothelial insult and vasculitis.[40][41][42]

Acute macular neuroretinopathy (AMN) and paracentral acute middle maculopathy (PAMM), conditions in which there is ischemia to the deep retinal capillary plexus, have also been observed with COVID, marked by hyperreflective changes at the level of the outer plexiform and inner nuclear layers.[43]

There have been two published case reports on Purtscher-like retinopathy observed in patients with COVID-19. Bottini et al. described a 59-year-old male who presented with multiple bilateral cotton wool spots localized to the posterior pole after a month-long hospitalization for COVID-19 pneumonia associated with multiorgan failure and severe coagulopathy.[44] Rahman and colleagues reported a 58-year-old male who presented with bilateral areas of ill-defined retinal whitening and arteriolar narrowing following a severe COVID-19 infection associated with disseminated intravascular coagulation.[45]

Optical coherence tomography (OCT) showed subclinical hyperreflective lesions at the level of the inner plexiform and ganglion cell layers in 12 adults examined after systemic disease onset; cotton wool spots and microhemorrhages were found on dilated fundus examinations in 4 of these patients.[46] Invernizzi and colleagues found retinal hemorrhages (9.25%), cotton wools spots (7.4%), dilated veins (27.7%), and tortuous vessels (12.9%) in 54 patients with COVID-19 upon screening with fundus photography.[47] These authors also found that retinal vein diameter correlated directly with disease severity, suggesting that this may be a non-invasive parameter to monitor inflammatory response and/or endothelial injury in COVID-19. Lecler et al. described abnormal MRI findings in the posterior pole of 9 patients with COVID-19 consisting of one or several hyperintense nodules in the macular region on FLAIR-weighted images.[48] These lesions were postulated to be either direct inflammatory infiltration of the retina or microangiopathic disease from viral infection.

Various forms of posterior uveitis have been observed following either acute COVID-19 infection or the COVID vaccine. Souza et al. reported a case of unilateral multifocal choroiditis, though it is noted that the temporal relationship of the viral infection could be attributed to chance alone.[49] Goyal et al. published a case of bilateral multifocal choroiditis within one week of the COVID-19 vaccine.[50] Cases of serpiginous and ampiginous choroiditis have also been reported.[51][52][51]

Immune dysregulation due to COVID-19 may contribute to the reactivation of latent herpervirus leading to acute retinal necrosis. This has been reported in two consecutive patients by Soni et al.[53]

Animal model studies have also shown the involvement of the retina with retinal vasculitis [54], retinal degeneration [55], and breakdown of the blood-retinal barrier.[56]

Optic Nerve

A wide variety of neuro-ophthalmologic manifestations have also been found in association with COVID-19, mostly related to demyelinating disease. While the mechanism of these manifestations is unknown, hypotheses include direct neuronal invasion, endothelial cell dysfunction leading to ischemia and coagulopathy, or a widespread inflammatory "cytokine storm" induced by the virus.[57] Optic neuritis has developed in several infected patients, presenting with neuromyelitis optica spectrum disorder and anti-myelin oligodendrocyte glycoprotein (anti-MOG) antibodies.[58][59][60] Patients presented with subacute vision loss, a relative afferent pupillary defect, pain with eye movements, optic disc edema, and radiographic findings of acute optic neuritis following a COVID-19 infection. There have also been reports of acute optic neuritis following vaccination for COVID-19.[61]

A case of multiple sclerosis following COVID-19 infection was reported by Palao et al. in a 24-year-old patient who presented with right optic neuritis; MRI demonstrated right optic nerve inflammation and supratentorial periventricular demyelinating lesions.[62] These cases suggest that SARS-CoV-2 can either trigger or exacerbate inflammatory and demyelinating disease.

Ophthalmologists may also be called to evaluate for papilledema in SARS-CoV-2 infected patients, as there have been cases of elevated intracranial pressure, both due to widespread inflammation and dural venous sinus thrombosis.[63] As previously mentioned, multisystem inflammatory syndrome in children (MIS-C) due to COVID-19 is also becoming recognized as a unique syndrome similar to Kawasaki disease and has been linked to both optic neuritis and elevated intracranial pressure.[64] Verkuli et al. described a case of a 14-year-old girl with pseudotumor cerebri syndrome associated with MIS-C due to COVID-19 manifesting as a new right abducens palsy, papilledema with disc hemorrhages, and lumbar puncture with an opening pressure of 36 cm H2O.[65]

Extraocular Motility, Cranial Nerves

Cranial nerve III, IV, and VI palsies associated with COVID-19 have been reported in the literature within a few days of fever and cough onset, most without remarkable radiological features.[66][67][68] Ocular cranial neuropathies and binocular diplopia with nerve enhancement on MRI have also been observed in association with post-infectious demyelinating conditions such as Miller Fisher and Guillain Barré syndrome. For example, Dinkin et al. described a 36-year-old male with left mydriasis, ptosis, and limited depression and adduction with concurrent MRI enhancement of the left oculomotor nerve.[69] He was also found to have lower extremity hyporeflexia and ataxia consistent with Miller Fisher syndrome.

Ocular myasthenia gravis has been described as a post-infectious sequela of COVID-19, with authors proposing that antibodies directed against SARS-CoV-2 proteins may cross-react with acetylcholine receptors and similar components at the neuromuscular junction.[70] Huber and colleagues described a 21-year-old patient who presented 4 weeks after COVID-19 infection with fluctuating vertical binocular diplopia and ptosis, treated successfully with intravenous immunoglobulins and oral pyridostigmine.[71]

Pupils

Pupillary changes have also been observed. Several groups have described patients with mydriasis and cholinergic super-sensitivity, indicative of tonic pupils and post-ganglionic parasympathetic pupillary nerve fiber damage.[72][73][74][73]

Nystagmus

Oscillopsia has been reported in several cases of COVID-19 with neurologic involvement. Malayala described a 20-year-old woman who presented with intractable vertigo, nausea, and vomiting with a presumed diagnosis of viral-induced vestibular neuritis secondary to COVID-19.[75] Central vestibular nystagmus has also been described in association with clinical and imaging findings consistent with rhombencephalitis.[76][77]

Visual Cortex

Perhaps the most devastating neuro-ophthalmic complication of severe COVID-19 infection is acute stroke affecting the posterior visual pathways. The incidence of stroke in these patients has been found to be 7.6 times higher than that of patients with influenza and has been occurring in a far younger than average patient population without classic vascular risk factors.[78] These patients may present with homonymous visual field deficits prompting ophthalmologic consultation. Authors at our university recently published a case of bilateral posterior cerebral artery ischemic strokes presenting as a homonymous visual field defect in a 12-year old patient with multisystem inflammatory syndrome related to COVID-19.[79]

Orbit and Ocular Adnexa

While oculoplastic and orbital manifestations of COVID-19 are uncommon, there is growing evidence to link inflammatory and infectious orbital disease to the virus. There have been two reported cases of sinusitis, orbital cellulitis, and intracranial abnormalities in adolescents with COVID-19.[80] It was postulated in this study at SARS-CoV-2 infection resulted in congestion of the upper respiratory tract and increased risk for secondary bacterial infection. This theory was expanded on by Shires et al., who reported a case of bacterial orbital abscess in a patient with COVID-19, with a unique intraoperative finding of highly avascular nasal mucosa and cultures positive for Streptococcus constellatus and Peptonipihilus indolicus, bacteria normally absent in the orbit or upper respiratory mucosa.[81] It is possible that the local microbiologic and immunologic environment was altered due to avascularity induced by thrombosis in the setting of SARS-CoV-2 infection.

There have been a growing number of reports of acute invasive fungal rhino-orbital mucormycosis co-infection with COVID-19. These opportunistic pathogens thrive in the hypoxic respiratory environment induced by SARS-CoV-2, as well as an immunocompromised state induced by high-dose steroids and immunosuppressive therapies. In patients with poorly controlled diabetes, particularly those with diabetic ketoacidosis (DKA), the risk is further increased.[82][83][84] Singh et al. published a systematic review of 101 reported cases of COVID-19 patients with mucormycosis; these patients were predominantly male (79%), 80% of which had diabetes and 15% with concomitant DKA.[85] Corticosteroids had been used in 76% of these patients and nearly 60% of the cases reported rhino-orbital involvement.[85] Another case described a 33-year-old female who presented with orbital compartment syndrome due to concurrent COVID-19 and fulminant mucormycotic infection.[86]

There have also been reports of MRI-proven orbital myositis in two separate COVID-19 patients in the absence of concomitant bacterial infection.[87][88][87] The authors postulated either direct viral orbital invasion or induced autoimmunity as possible mechanisms.

Similar processes have been proposed by Diaz et al., who reported a case of acute dacryoadenitis in a 22-year-old male with positive SARS-CoV-2 antibodies who developed partial ophthalmoplegia.[89] Providers at our university have treated one patient with typical symptoms and signs of dacryoadenitis occurring concurrently with a positive COVID-19 nasopharyngeal test. The patient responded to a slow taper of steroids over six weeks. A recently submitted cases series by our group also highlights a case of biopsy-proven chronic dacryoadenitis in a 57-year-old man with COVID-19, with symptom onset one month following his viral symptoms. Other cases in this series include idiopathic inflammation in an anophthalmic socket.

Lacrimal System

Epiphora has been described as an initial finding in patients with COVID-19.[12] This is thought to be secondary epiphora from inflammation of the conjunctiva. Direct involvement of the nasolacrimal system or the lacrimal sac has not been reported to date. 

Manifestations in Newborn Infants

There have been recent data to support frequent ocular manifestations of SARS-CoV-2 infection in newborn infants. In a study by Perez-Chimal et al. in Mexico, 15 infants were identified with positive RT-PCR nasopharyngeal swabs. All of these newborns exhibited ocular manifestations, most commonly periorbital edema (100%), followed by chemosis and hemorrhagic conjunctivitis (73%) and ciliary injection (53%). Unique findings included 6 infants (40%) with corneal edema, 1 with rubeosis and posterior synechiae, and posterior segment manifestations including retinopathy of prematurity in 3 (20%) infants.[90] Vitreous hemorrhage was observed in 1 full-term baby and subtle cotton wool spots in 2 other newborns.

Evaluation

A thorough history is necessary regarding the onset, duration, and characteristics of symptoms. Anterior segment examination at the slit lamp or bedside can confirm findings of conjunctivitis or episcleritis. Measurement of visual acuity, intraocular pressure, and dilated fundus examination are warranted to rule out potentially more harmful ocular diseases. The clinician should perform a careful examination of pupils and color testing to evaluate patients for evidence of optic neuropathy. Evaluation of extraocular motility may show evidence of nystagmus or cranial neuropathies. Visual field testing can detect and confirm deficits related to stroke.

SARS-CoV-2 can be detected in RT-PCR by sweeping the lower eyelid fornices to collect tears and conjunctival secretions with a virus sampling swab.[13] Additional serum or cerebrospinal fluid testing may be useful to evaluate for inflammatory, autoimmune, or demyelinating entities. Neuroimaging can be valuable in patients presenting with optic neuritis, visual field deficits, cranial neuropathies, or other associated neurologic symptoms.

All patients should be questioned about recent fever, respiratory symptoms, exposure, and travel history to assess the need for further evaluation of COVID-19. 

Treatment / Management

Chen et al. reported gradual symptomatic improvement of COVID-19 conjunctivitis in one patient with administration of ribavirin eye drops.[91] The efficacy of targeted treatment has not been studied. It is unlikely to be of long-term clinical importance in a self-limited viral illness. However, eye care providers should be mindful of trying to decrease possible viral load and potential transmission.[92]

As with other viral infections, COVID-19 conjunctivitis is presumed to be self-limited and can be managed with symptomatic care. In the absence of significant eye pain, decreased vision, or light sensitivity, many patients can be managed remotely with a trial of frequent preservative-free artificial tears, cold compresses, and lubricating ophthalmic ointment. A short course of topical antibiotics can prevent or treat bacterial superinfection based on the patient's symptoms and risk factors (e.g. contact lens wear).[93] 

On March 18, 2020, the American Academy of Ophthalmology (AAO) urged all ophthalmologists to provide only urgent or emergent care to reduce the risk of SARS-CoV-2 transmission and to conserve disposable medical supplies. Specific criteria are presented below. In the summer of 2020, many centers had begun to resume elective surgeries and consider expanding care on a case-by-case basis based on reopening guidelines from the federal government. 

Although preliminary studies suggest that the risk of viral transmission through ocular secretions is low, large-scale research has not yet been done, and new data is emerging daily. Therefore, healthcare providers are still urged to wear proper protection of the eyes, nose, and mouth when examining patients (see below). Eye care providers and technicians may be more susceptible to infection due to the nature and proximity of the ophthalmic examination.[94] Eye care providers are encouraged to use slit lamp breath shields and should counsel patients to speak as little as possible when sitting at the slit lamp to reduce the risk of virus transmission. Disinfection and sterilization practices should be employed for shared clinic equipment such as tonometers, trial frames, pinhole occluders, B-scan probes, and contact lenses for laser procedures.[2][94] Disposable barrier protection of clinic tools should be used where possible.

Stratification of Ophthalmic Patients for Clinic Visits from early 2020 to December 2020

In the presence of life-threatening infections such as this, ophthalmologists have to achieve a balance between providing ophthalmic care and infection control. Most ophthalmic conditions are not life-threatening. Furthermore, many can be managed with some delay in treatment as they progress relatively slowly (cataracts, glaucoma, ptosis, etc.). However, some conditions like retinal detachments, acute infections (cellulitis, orbital cellulitis), severe inflammation (uveitis), and trauma require more urgent attention. To that end, the following is suggested for the management of ophthalmic patients:

1. All routine ophthalmic patients are delayed until the severity of disease spread reduces as determined by the WHO and the local Chief Medical Officer. These include chronic conditions and routine clinic annual and other follow-ups as well as new patients with chronic conditions like cataracts, ptosis, etc. 

2. New patient referrals are reviewed by the consultant surgeon to determine urgency. If necessary, telephone interviews with the referring doctor and/or the patient are held. 

3. All patients considered for a clinic visit are reviewed for three things: 

  • Presence of fever, cough, or shortness of breath
  • Any foreign travel or travel to an area with a high infection rate within the prior 14 days
  • Any contact with patients who have been diagnosed as having COVID-19

The presence of any of these would be a reason to consider the necessity of seeing and examining the patient more closely. If a patient has two of the three are referred for medical assessment. If a patient with COVID-19 or one with a fever, cough, or shortness of breath needs to be examined, the patient is seen in a separate isolation room. Ideally, only one person (physician, technician, etc.) should be present in the room (as ophthalmic rooms tend to be small) and should wear the full personal protective equipment (PPE): gown, N95 mask, face shield, and gloves. Hands are washed before and after examination for a minimum of 20 seconds with soap and water. Once the ophthalmic examination is completed, the patient is referred for further assessment by the medical team. 

Protection of Medical Workers

Although the 2003 SARS-CoV crisis did not create quite so severe a spread of infection in the United States, it was noted that health care workers (HCW) accounted for about 20% of all patients with infections.[95] Most recent figures show that HCWs make up 9% of Italy's COVID-19 cases. In the United States, between March 2020 and April 7. 2021, more than 3699 health workers have died from COVID-19 infections with the majority being younger than 60 years of age. As of April 7, 2021, the number of coronavirus cases recorded among healthcare workers in Italy reached 129,873.  Early in the pandemic in Italy, by April 2020, more than 100 health care workers had died from COVID-19 infections, including, more than 60 doctors. Current figures are not available and figures in other countries will continue to increase. 

It is, therefore, vital that front-line medical workers wear proper protection. Secondly, it is important to monitor these health care workers for disease and implement appropriate containment measures. 

A significant number of deaths in the United States were associated with an initial severe shortage of appropriate personal protective equipment for healthcare providers. Even with the availability of appropriate protective equipment, it behooves us to choose the level of protective gear based upon the risk of infection. The following is suggested:

  • Keep the waiting room as empty as possible with available seating spaced at least 6 feet apart.
  • For all patients who have none of the three criteria mentioned above, the medical workers will wear a surgical mask, a face shield, and gloves. Hands are washed before and after every encounter.
  • If a patient is positive for any of the three criteria, the full PPE of gown, face shield, gloves, and the N95 mask are worn. 
  • It has been noted that droplets from sneezes can travel up to 6 meters.[96] To that end, inventive ophthalmic technicians at the Moran Eye Center have developed a slit-lamp shield made by passing two plastic sheets through a laminator without a paper in between and cutting openings for the eyepieces (Fig 1). Others have similarly used old X-ray films when commercially available shields are in short supply. 
  • Conversations are kept to a minimum during the consultation. Ophthalmologists are, by nature, a gregarious lot. Such temptations are to be resisted. 
  • As a shortage of surgical masks has become a reality, some institutions are storing used masks at the end of each day in a container with a view to re-sterilization if necessary. 
  • As many as a quarter of patients being injected under sedation may develop a severe involuntary sneeze.[97][98] This is more common with eyelid injections than with retrobulbar injections. Ophthalmic surgeons should be acutely aware of this to take appropriate precautions during the administration of the local anesthetic. 

Surveillance of Medical Workers

  • In Singapore, health workers reported their temperatures twice a day via an online system: this was eminently sensible as the "walk-by" temperature-testing that was practiced may not be as accurate or complete with staff arriving early, leaving late, etc.[99] As of April 16, 2021, Singapore had had 60,769 infections and only 30 deaths caused by the virus. 
  • All travel outside the state or country should be declared to the medical administration for review. This should still apply in April 2021 as there are recurring hot spots of infection in different states and countries. 
  • All health workers should self-report any symptoms, so appropriate testing may be performed: isolation and contact-tracing would then be undertaken as deemed necessary. 

Sterilization of Equipment

  • The slit-lamp shields are disinfected with 70% ethyl alcohol after each patient; 70% ethyl alcohol has been shown to reduce coronavirus infectivity.[96]
  • Slitlamps, B-scan probes, and any other tools are similarly cleaned with 70% ethyl alcohol.
  • Goldman tonometers are sterilized with a 10% diluted sodium hypochlorite solution, which inactivates coronaviruses.[100]

Differential Diagnosis

Ocular manifestations of COVID-19 have most commonly presented with conjunctivitis otherwise indistinguishable from other viral etiologies. Differential diagnosis includes a broad range of common ocular manifestations of eye redness and increased tearing:

  • Other viral conjunctivitis (e.g., adenovirus)
  • Bacterial conjunctivitis
  • Allergic conjunctivitis
  • Herpes simplex virus keratitis
  • Anterior uveitis
  • Corneal abrasion
  • Foreign body
  • Dry eye syndrome
  • Exposure keratopathy in an intubated patient
  • Chemosis in a critically ill patient

Prognosis

Conjunctivitis related to COVID-19 is currently thought to be self-limited. Larger studies and long-term follow-up of patients with other ocular manifestations COVID-19 have yet to be reported. Globally, we are in the grip of grim circumstances with ebbs and flows of infections. With the rather disjointed global response to the infection and unbalanced vaccine administration, the hope that out of the pain joy will spring and new strengths arise from recognition of the weaknesses of administrations around the world is a distant hope. 

Complications

Sequelae and complications from demyelinating disease and stroke require management in conjunction with other specialties such as neurology, occupational therapy, and physical medicine and rehabilitation. Ophthalmologists need to be vigilant as we continue to learn of the different ways that COVID-19 may affect the eye and periorbital tissues. 

Deterrence and Patient Education

Prevention strategies are vital to limiting the spread of disease. In addition to physical distancing and practicing good hand-washing hygiene, patients should employ behavioral changes that reduce the direct touching of the eyes and face. These are "soft" suggestions which are mostly ignored now that vaccinations are becoming available and infections in parts of the world are decreasing.

  • Refraining from wearing contact lenses during the outbreak
  • Refraining from applying cosmetics
  • Wearing glasses and sunglasses
  • Changing sheets, pillowcases, and towels regularly

Pearls and Other Issues

  • Ocular shedding of SARS-CoV-2 via tears is a distinct possibility of which ophthalmologists should be aware.
  • Conjunctivitis or tearing can be the first presentation and even sole manifestation in a patient with the COVID-19 infection.
  • Several ocular manifestations of COVID-19 have been observed, including retinovascular disease, uveitis, optic neuropathies, and orbital fungal co-infections.
  • SARS-CoV-2 may trigger or exacerbate inflammatory/demyelinating disease.
  • Patients may present with chemosis in advanced cases (Fig 2) or follicular conjunctivitis (Fig 3).
  • The ocular examination should be performed while wearing gloves and using extension instruments (cotton swabs, etc.) to avoid direct contact with secretions.
  • As many patients who visit the ophthalmic clinic are elderly, many with comorbidities, it is important to screen the need for the visit ahead of time and only see patients who need urgent care. We continue to practice telemedicine for many of these patients. 
  • As advocated in many countries, social distancing means being 6 feet away from others: this is clearly impossible in the clinical world and certainly in the small confines of ophthalmic examination lanes. One way to practice it is to have only one person in the room with the patient.
  • Anecdotally, it has been observed that physicians most at risk of becoming infected include ophthalmologists, otolaryngologists, and anesthesiologists because of the proximity of the examiners to mucosal surfaces.
  • When performing surgery under general anesthesia, it has been recommended that surgeons and other staff do not enter the room for 15 minutes after intubation or extubation. This standard is applied to all general anesthesia cases in many facilities, whether the patient is COVID-19 positive or negative.

Enhancing Healthcare Team Outcomes

Within outpatient, inpatient, and surgical settings, an interprofessional approach is necessary to manage COVID-19 patients and successfully mitigate the spread of disease.

There should be clear communication between hospital administration, provider teams, and clinic support staff regarding expectations for screening patients, wearing personal protective equipment, and utilizing new technologies for telemedicine consultations. [Level 5 evidence]



(Click Image to Enlarge)
This illustration, created at the Centers for Disease Control and Prevention (CDC), reveals ultrastructural morphology exhibited by coronaviruses. Note the spikes that adorn the outer surface of the virus, which impart the look of a corona surrounding the virion, when viewed electron microscopically. In this view, the protein particles E, S, and M, also located on the outer surface of the particle, have all been labeled as well. A novel coronavirus, named Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), was identified as the cause of an outbreak of respiratory illness first detected in Wuhan, China in 2019. The illness caused by this virus has been named coronavirus disease 2019 (COVID-19).
This illustration, created at the Centers for Disease Control and Prevention (CDC), reveals ultrastructural morphology exhibited by coronaviruses. Note the spikes that adorn the outer surface of the virus, which impart the look of a corona surrounding the virion, when viewed electron microscopically. In this view, the protein particles E, S, and M, also located on the outer surface of the particle, have all been labeled as well. A novel coronavirus, named Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), was identified as the cause of an outbreak of respiratory illness first detected in Wuhan, China in 2019. The illness caused by this virus has been named coronavirus disease 2019 (COVID-19).
Contributed from the CDC, Alissa Eckert, MS; Dan Higgins, MAM (Public Domain)

(Click Image to Enlarge)
A slit-lamp shield to protect the examiner as designed by Moran Technicians Stein Erickson, Emily Petersen and Anna Reed together with help from others: made by passing two lamination sheets together through a laminator without anything inbetween. Results in a rigid shield which can be cleaned with alcohol and reused. Other materials that may be used include used X-Ray films but these do not have the clarity needed.
A slit-lamp shield to protect the examiner as designed by Moran Technicians Stein Erickson, Emily Petersen and Anna Reed together with help from others: made by passing two lamination sheets together through a laminator without anything inbetween. Results in a rigid shield which can be cleaned with alcohol and reused. Other materials that may be used include used X-Ray films but these do not have the clarity needed.
Contributed on behalf of the Moran Eye Center by Dr. Katherine Hu MD and Prof. BCK Patel MD, FRCS

(Click Image to Enlarge)
Chemosis: conjunctival edema and inflammation. Can be seen with viral and bacterial infections, after eyelid surgery, trauma, thyroid disease and orbital tumors
Chemosis: conjunctival edema and inflammation. Can be seen with viral and bacterial infections, after eyelid surgery, trauma, thyroid disease and orbital tumors
Contributed by Prof. BCK Patel MD, FRCS

(Click Image to Enlarge)
Follicular conjunctivitis may be seen with viral infections like herpes zoster, Epstein-Barr virus infection, infectious mononucleosis), chlamydial infections, and in reaction of topical medications and molluscum contagiosum. Follicular conjunctivitis has been described in patients with the COVID-19 infection (coronavirus infection). The inferior and superior tarsal conjunctiva and the fornices show gray-white elevated swellings which are about 0.5 - 1 mm in diameter and have a velvety appearance
Follicular conjunctivitis may be seen with viral infections like herpes zoster, Epstein-Barr virus infection, infectious mononucleosis), chlamydial infections, and in reaction of topical medications and molluscum contagiosum. Follicular conjunctivitis has been described in patients with the COVID-19 infection (coronavirus infection). The inferior and superior tarsal conjunctiva and the fornices show gray-white elevated swellings which are about 0.5 - 1 mm in diameter and have a velvety appearance
Contributed by Prof. Bhupendra C. K. Patel MD, FRCS

(Click Image to Enlarge)
Color photography and fluorescein angiography of a patient with fungal endophthalmitis following coronavirus disease-2019.
Color photography and fluorescein angiography of a patient with fungal endophthalmitis following coronavirus disease-2019.
Contributed by Gehad Elnahry, MD
Article Details

Article Author

Katherine Hu

Article Author

Jay Patel

Article Author

Cole Swiston

Article Editor:

Bhupendra Patel

Updated:

1/8/2022 9:50:15 AM

References

[1]

Cascella M,Rajnik M,Cuomo A,Dulebohn SC,Di Napoli R, Features, Evaluation and Treatment Coronavirus (COVID-19) 2020 Jan;     [PubMed PMID: 32150360]

[2]

Loon SC,Teoh SC,Oon LL,Se-Thoe SY,Ling AE,Leo YS,Leong HN, The severe acute respiratory syndrome coronavirus in tears. The British journal of ophthalmology. 2004 Jul;     [PubMed PMID: 15205225]

[3]

Raboud J,Shigayeva A,McGeer A,Bontovics E,Chapman M,Gravel D,Henry B,Lapinsky S,Loeb M,McDonald LC,Ofner M,Paton S,Reynolds D,Scales D,Shen S,Simor A,Stewart T,Vearncombe M,Zoutman D,Green K, Risk factors for SARS transmission from patients requiring intubation: a multicentre investigation in Toronto, Canada. PloS one. 2010 May 19;     [PubMed PMID: 20502660]

[4]

Lu CW,Liu XF,Jia ZF, 2019-nCoV transmission through the ocular surface must not be ignored. Lancet (London, England). 2020 Feb 22;     [PubMed PMID: 32035510]

[5]

Azzolini C,Donati S,Premi E,Baj A,Siracusa C,Genoni A,Grossi PA,Azzi L,Sessa F,Dentali F,Severgnini P,Minoja G,Cabrini L,Chiaravalli M,Veronesi G,Carcano G,Maffioli LS,Tagliabue A, SARS-CoV-2 on Ocular Surfaces in a Cohort of Patients With COVID-19 From the Lombardy Region, Italy. JAMA ophthalmology. 2021 Mar 4     [PubMed PMID: 33662099]

[6]

Seah I,Agrawal R, Can the Coronavirus Disease 2019 (COVID-19) Affect the Eyes? A Review of Coronaviruses and Ocular Implications in Humans and Animals. Ocular immunology and inflammation. 2020 Mar 16;     [PubMed PMID: 32175797]

[7]

Li JO,Lam DSC,Chen Y,Ting DSW, Novel Coronavirus disease 2019 (COVID-19): The importance of recognising possible early ocular manifestation and using protective eyewear. The British journal of ophthalmology. 2020 Mar;     [PubMed PMID: 32086236]

[8]

Shiehzadegan S,Alaghemand N,Fox M,Venketaraman V, Analysis of the Delta Variant B.1.617.2 COVID-19. Clinics and practice. 2021 Oct 21;     [PubMed PMID: 34698149]

[9]

Ferré VM,Peiffer-Smadja N,Visseaux B,Descamps D,Ghosn J,Charpentier C, Omicron SARS-CoV-2 variant: What we know and what we don't. Anaesthesia, critical care     [PubMed PMID: 34902630]

[10]

Guan WJ,Ni ZY,Hu Y,Liang WH,Ou CQ,He JX,Liu L,Shan H,Lei CL,Hui DSC,Du B,Li LJ,Zeng G,Yuen KY,Chen RC,Tang CL,Wang T,Chen PY,Xiang J,Li SY,Wang JL,Liang ZJ,Peng YX,Wei L,Liu Y,Hu YH,Peng P,Wang JM,Liu JY,Chen Z,Li G,Zheng ZJ,Qiu SQ,Luo J,Ye CJ,Zhu SY,Zhong NS, Clinical Characteristics of Coronavirus Disease 2019 in China. The New England journal of medicine. 2020 Feb 28;     [PubMed PMID: 32109013]

[11]

Nasiri N,Sharifi H,Bazrafshan A,Noori A,Karamouzian M,Sharifi A, Ocular Manifestations of COVID-19: A Systematic Review and Meta-analysis. Journal of ophthalmic     [PubMed PMID: 33520133]

[12]

Wu P,Duan F,Luo C,Liu Q,Qu X,Liang L,Wu K, Characteristics of Ocular Findings of Patients With Coronavirus Disease 2019 (COVID-19) in Hubei Province, China. JAMA ophthalmology. 2020 Mar 31;     [PubMed PMID: 32232433]

[13]

Xia J,Tong J,Liu M,Shen Y,Guo D, Evaluation of coronavirus in tears and conjunctival secretions of patients with SARS-CoV-2 infection. Journal of medical virology. 2020 Feb 26;     [PubMed PMID: 32100876]

[14]

Harrison AG,Lin T,Wang P, Mechanisms of SARS-CoV-2 Transmission and Pathogenesis. Trends in immunology. 2020 Dec;     [PubMed PMID: 33132005]

[15]

Zhou L,Xu Z,Castiglione GM,Soiberman US,Eberhart CG,Duh EJ, ACE2 and TMPRSS2 are expressed on the human ocular surface, suggesting susceptibility to SARS-CoV-2 infection. bioRxiv : the preprint server for biology. 2020 May 9;     [PubMed PMID: 32511393]

[16]

Lange C,Wolf J,Auw-Haedrich C,Schlecht A,Boneva S,Lapp T,Horres R,Agostini H,Martin G,Reinhard T,Schlunck G, Expression of the COVID-19 receptor ACE2 in the human conjunctiva. Journal of medical virology. 2020 Oct;     [PubMed PMID: 32374427]

[17]

Colavita F,Lapa D,Carletti F,Lalle E,Bordi L,Marsella P,Nicastri E,Bevilacqua N,Giancola ML,Corpolongo A,Ippolito G,Capobianchi MR,Castilletti C, SARS-CoV-2 Isolation From Ocular Secretions of a Patient With COVID-19 in Italy With Prolonged Viral RNA Detection. Annals of internal medicine. 2020 Aug 4;     [PubMed PMID: 32302380]

[18]

Chen MJ,Chang KJ,Hsu CC,Lin PY,Jui-Ling Liu C, Precaution and prevention of coronavirus disease 2019 infection in the eye. Journal of the Chinese Medical Association : JCMA. 2020 Jul;     [PubMed PMID: 32332516]

[19]

Dockery DM,Rowe SG,Murphy MA,Krzystolik MG, The Ocular Manifestations and Transmission of COVID-19: Recommendations for Prevention. The Journal of emergency medicine. 2020 Jul;     [PubMed PMID: 32456959]

[20]

Jevnikar K,Jaki Mekjavic P,Vidovic Valentincic N,Petrovski G,Globocnik Petrovic M, An Update on COVID-19 Related Ophthalmic Manifestations. Ocular immunology and inflammation. 2021 Apr 7     [PubMed PMID: 33826465]

[21]

Kumar KK,Sampritha UC,Prakash AA,Adappa K,Chandraprabha S,Neeraja TG,Guru Prasad NS,Basumatary J,Gangasagara SB,Sujatha Rathod BL,Jayanthi CR, Ophthalmic manifestations in the COVID-19 clinical spectrum. Indian journal of ophthalmology. 2021 Mar     [PubMed PMID: 33595502]

[22]

Soltani S,Tabibzadeh A,Zakeri A,Zakeri AM,Latifi T,Shabani M,Pouremamali A,Erfani Y,Pakzad I,Malekifar P,Valizadeh R,Zandi M,Pakzad R, COVID-19 associated central nervous system manifestations, mental and neurological symptoms: a systematic review and meta-analysis. Reviews in the neurosciences. 2021 Apr 27     [PubMed PMID: 33618441]

[23]

Sen M,Honavar SG,Sharma N,Sachdev MS, COVID-19 and Eye: A Review of Ophthalmic Manifestations of COVID-19. Indian journal of ophthalmology. 2021 Mar     [PubMed PMID: 33595463]

[24]

Domínguez-Varela IA,Rodríguez-Gutiérrez LA,Morales-Mancillas NR,Barrera-Sánchez M,Macías-Rodríguez Y,Valdez-García JE, COVID-19 and the eye: a review. Infectious diseases (London, England). 2021 Jun     [PubMed PMID: 33566704]

[25]

Ulhaq ZS,Soraya GV, The prevalence of ophthalmic manifestations in COVID-19 and the diagnostic value of ocular tissue/fluid. Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie. 2020 Jun     [PubMed PMID: 32328758]

[26]

Scalinci SZ,Trovato Battagliola E, Conjunctivitis can be the only presenting sign and symptom of COVID-19. IDCases. 2020;     [PubMed PMID: 32373467]

[27]

Cheema M,Aghazadeh H,Nazarali S,Ting A,Hodges J,McFarlane A,Kanji JN,Zelyas N,Damji KF,Solarte C, Keratoconjunctivitis as the initial medical presentation of the novel coronavirus disease 2019 (COVID-19). Canadian journal of ophthalmology. Journal canadien d'ophtalmologie. 2020 Aug;     [PubMed PMID: 32284146]

[28]

Navel V,Chiambaretta F,Dutheil F, Haemorrhagic conjunctivitis with pseudomembranous related to SARS-CoV-2. American journal of ophthalmology case reports. 2020 Sep;     [PubMed PMID: 32377594]

[29]

Danthuluri V,Grant MB, Update and Recommendations for Ocular Manifestations of COVID-19 in Adults and Children: A Narrative Review. Ophthalmology and therapy. 2020 Dec;     [PubMed PMID: 33058068]

[30]

Otaif W,Al Somali AI,Al Habash A, Episcleritis as a possible presenting sign of the novel coronavirus disease: A case report. American journal of ophthalmology case reports. 2020 Dec;     [PubMed PMID: 32923742]

[31]

Méndez Mangana C,Barraquer Kargacin A,Barraquer RI, Episcleritis as an ocular manifestation in a patient with COVID-19. Acta ophthalmologica. 2020 Dec;     [PubMed PMID: 32483943]

[32]

Feizi S,Meshksar A,Naderi A,Esfandiari H, Anterior Scleritis Manifesting After Coronavirus Disease 2019: A Report of Two Cases. Cornea. 2021 Sep 1;     [PubMed PMID: 34351874]

[33]

Mazzotta C,Giancipoli E, Anterior Acute Uveitis Report in a SARS-CoV-2 Patient Managed with Adjunctive Topical Antiseptic Prophylaxis Preventing 2019-nCoV Spread Through the Ocular Surface Route. International medical case reports journal. 2020;     [PubMed PMID: 33116943]

[34]

Bettach E,Zadok D,Weill Y,Brosh K,Hanhart J, Bilateral anterior uveitis as a part of a multisystem inflammatory syndrome secondary to COVID-19 infection. Journal of medical virology. 2021 Jan;     [PubMed PMID: 32592496]

[35]

Sanjay S,Mutalik D,Gowda S,Mahendradas P,Kawali A,Shetty R,     [PubMed PMID: 34124585]

[36]

Zhou L,Xu Z,Guerra J,Rosenberg AZ,Fenaroli P,Eberhart CG,Duh EJ, Expression of the SARS-CoV-2 Receptor ACE2 in Human Retina and Diabetes-Implications for Retinopathy. Investigative ophthalmology     [PubMed PMID: 34086044]

[37]

Araujo-Silva CA,Marcos AAA,Marinho PM,Branco AMC,Roque A,Romano AC,Matuoka ML,Farah M,Burnier M,Moraes NF,Tierno PFGMM,Schor P,Sakamoto V,Nascimento H,de Sousa W,Belfort R Jr, Presumed SARS-CoV-2 Viral Particles in the Human Retina of Patients With COVID-19. JAMA ophthalmology. 2021 Sep 1;     [PubMed PMID: 34323931]

[38]

Walinjkar JA,Makhija SC,Sharma HR,Morekar SR,Natarajan S, Central retinal vein occlusion with COVID-19 infection as the presumptive etiology. Indian journal of ophthalmology. 2020 Nov;     [PubMed PMID: 33120696]

[39]

Yahalomi T,Pikkel J,Arnon R,Pessach Y, Central retinal vein occlusion in a young healthy COVID-19 patient: A case report. American journal of ophthalmology case reports. 2020 Dec;     [PubMed PMID: 33225111]

[40]

Acharya S,Diamond M,Anwar S,Glaser A,Tyagi P, Unique case of central retinal artery occlusion secondary to COVID-19 disease. IDCases. 2020;     [PubMed PMID: 32572363]

[41]

Montesel A,Bucolo C,Mouvet V,Moret E,Eandi CM, Case Report: Central Retinal Artery Occlusion in a COVID-19 Patient. Frontiers in pharmacology. 2020;     [PubMed PMID: 33424598]

[42]

Murchison AP,Sweid A,Dharia R,Theofanis TN,Tjoumakaris SI,Jabbour PM,Bilyk JR, Monocular visual loss as the presenting symptom of COVID-19 infection. Clinical neurology and neurosurgery. 2021 Feb;     [PubMed PMID: 33383464]

[43]

Gascon P,Briantais A,Bertrand E,Ramtohul P,Comet A,Beylerian M,Sauvan L,Swiader L,Durand JM,Denis D, Covid-19-Associated Retinopathy: A Case Report. Ocular immunology and inflammation. 2020 Nov 16;     [PubMed PMID: 33021856]

[44]

Bottini AR,Steinmetz S,Blinder KJ,Shah GK, Purtscher-Like Retinopathy in a Patient with COVID-19. Case reports in ophthalmological medicine. 2021;     [PubMed PMID: 33859855]

[45]

Rahman EZ,Shah P,Ong JE,Goldberg M,Ong SS, Purtscher-like retinopathy in a patient with COVID-19 and disseminated intravascular coagulation. American journal of ophthalmology case reports. 2021 Dec;     [PubMed PMID: 34796309]

[46]

Marinho PM,Marcos AAA,Romano AC,Nascimento H,Belfort R Jr, Retinal findings in patients with COVID-19. Lancet (London, England). 2020 May 23;     [PubMed PMID: 32405105]

[47]

Invernizzi A,Torre A,Parrulli S,Zicarelli F,Schiuma M,Colombo V,Giacomelli A,Cigada M,Milazzo L,Ridolfo A,Faggion I,Cordier L,Oldani M,Marini S,Villa P,Rizzardini G,Galli M,Antinori S,Staurenghi G,Meroni L, Retinal findings in patients with COVID-19: Results from the SERPICO-19 study. EClinicalMedicine. 2020 Oct;     [PubMed PMID: 32984785]

[48]

Lecler A,Cotton F,Lersy F,Kremer S,Héran F,SFNR’s COVID Study Group., Ocular MRI Findings in Patients with Severe COVID-19: A Retrospective Multicenter Observational Study. Radiology. 2021 Feb 16;     [PubMed PMID: 33591889]

[49]

de Souza EC,de Campos VE,Duker JS, Atypical unilateral multifocal choroiditis in a COVID-19 positive patient. American journal of ophthalmology case reports. 2021 Jun;     [PubMed PMID: 33623832]

[50]

Goyal M,Murthy SI,Annum S, Bilateral Multifocal Choroiditis following COVID-19 Vaccination. Ocular immunology and inflammation. 2021 May 19;     [PubMed PMID: 34344280]

[51]

Providência J,Fonseca C,Henriques F,Proença R, Serpiginous choroiditis presenting after SARS-CoV-2 infection: A new immunological trigger? European journal of ophthalmology. 2020 Dec 2;     [PubMed PMID: 33267645]

[52]

Tom ES,McKay KM,Saraf SS, Bilateral Ampiginous Choroiditis following Presumed SARS-CoV-2 Infection. Case reports in ophthalmological medicine. 2021;     [PubMed PMID: 34367705]

[53]

Soni A,Narayanan R,Tyagi M,Belenje A,Basu S, Acute Retinal Necrosis as a presenting ophthalmic manifestation in COVID 19 recovered patients. Ocular immunology and inflammation. 2021 May 19;     [PubMed PMID: 34228583]

[54]

Chin MS,Hooper LC,Hooks JJ,Detrick B, Identification of α-fodrin as an autoantigen in experimental coronavirus retinopathy (ECOR). Journal of neuroimmunology. 2014 Jul 15     [PubMed PMID: 24864013]

[55]

Wang Y,Detrick B,Yu ZX,Zhang J,Chesky L,Hooks JJ, The role of apoptosis within the retina of coronavirus-infected mice. Investigative ophthalmology & visual science. 2000 Sep     [PubMed PMID: 10967058]

[56]

Vinores SA,Wang Y,Vinores MA,Derevjanik NL,Shi A,Klein DA,Detrick B,Hooks JJ, Blood-retinal barrier breakdown in experimental coronavirus retinopathy: association with viral antigen, inflammation, and VEGF in sensitive and resistant strains. Journal of neuroimmunology. 2001 Oct 1     [PubMed PMID: 11585619]

[57]

Luís ME,Hipólito-Fernandes D,Mota C,Maleita D,Xavier C,Maio T,Cunha JP,Tavares Ferreira J, A Review of Neuro-Ophthalmological Manifestations of Human Coronavirus Infection. Eye and brain. 2020;     [PubMed PMID: 33154692]

[58]

Sawalha K,Adeodokun S,Kamoga GR, COVID-19-Induced Acute Bilateral Optic Neuritis. Journal of investigative medicine high impact case reports. 2020 Jan-Dec;     [PubMed PMID: 33238757]

[59]

Zhou S,Jones-Lopez EC,Soneji DJ,Azevedo CJ,Patel VR, Myelin Oligodendrocyte Glycoprotein Antibody-Associated Optic Neuritis and Myelitis in COVID-19. Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society. 2020 Sep;     [PubMed PMID: 32604245]

[60]

de Ruijter NS,Kramer G,Gons RAR,Hengstman GJD, Neuromyelitis optica spectrum disorder after presumed coronavirus (COVID-19) infection: A case report. Multiple sclerosis and related disorders. 2020 Nov;     [PubMed PMID: 32892062]

[61]

Leber HM,Sant'Ana L,Konichi da Silva NR,Raio MC,Mazzeo TJMM,Endo CM,Nascimento H,de Souza CE, Acute Thyroiditis and Bilateral Optic Neuritis following SARS-CoV-2 Vaccination with CoronaVac: A Case Report. Ocular immunology and inflammation. 2021 Aug 17;     [PubMed PMID: 34402726]

[62]

Palao M,Fernández-Díaz E,Gracia-Gil J,Romero-Sánchez CM,Díaz-Maroto I,Segura T, Multiple sclerosis following SARS-CoV-2 infection. Multiple sclerosis and related disorders. 2020 Oct;     [PubMed PMID: 32698095]

[63]

Cavalcanti DD,Raz E,Shapiro M,Dehkharghani S,Yaghi S,Lillemoe K,Nossek E,Torres J,Jain R,Riina HA,Radmanesh A,Nelson PK, Cerebral Venous Thrombosis Associated with COVID-19. AJNR. American journal of neuroradiology. 2020 Aug;     [PubMed PMID: 32554424]

[64]

Baccarella A,Linder A,Spencer R,Jonokuchi AJ,King PB,Maldonado-Soto A,Boneparth A,Hooe BS,Schweickert AJ,Carlin RF,Kingery F,Vargas WS,Sewell TB,Silver WG, Increased Intracranial Pressure in the Setting of Multisystem Inflammatory Syndrome in Children, Associated With COVID-19. Pediatric neurology. 2021 Feb;     [PubMed PMID: 33333460]

[65]

Verkuil LD,Liu GT,Brahma VL,Avery RA, Pseudotumor cerebri syndrome associated with MIS-C: a case report. Lancet (London, England). 2020 Aug 22;     [PubMed PMID: 32795406]

[66]

Belghmaidi S,Nassih H,Boutgayout S,El Fakiri K,El Qadiry R,Hajji I,Bourrahouate A,Moutaouakil A, Third Cranial Nerve Palsy Presenting with Unilateral Diplopia and Strabismus in a 24-Year-Old Woman with COVID-19. The American journal of case reports. 2020 Oct 15;     [PubMed PMID: 33056942]

[67]

Oliveira RMC,Santos DH,Olivetti BC,Takahashi JT, Bilateral trochlear nerve palsy due to cerebral vasculitis related to COVID-19 infection. Arquivos de neuro-psiquiatria. 2020 Jun;     [PubMed PMID: 32609196]

[68]

Greer CE,Bhatt JM,Oliveira CA,Dinkin MJ, Isolated Cranial Nerve 6 Palsy in 6 Patients With COVID-19 Infection. Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society. 2020 Dec;     [PubMed PMID: 32941331]

[69]

Dinkin M,Gao V,Kahan J,Bobker S,Simonetto M,Wechsler P,Harpe J,Greer C,Mints G,Salama G,Tsiouris AJ,Leifer D, COVID-19 presenting with ophthalmoparesis from cranial nerve palsy. Neurology. 2020 Aug 4;     [PubMed PMID: 32358218]

[70]

Restivo DA,Centonze D,Alesina A,Marchese-Ragona R, Myasthenia Gravis Associated With SARS-CoV-2 Infection. Annals of internal medicine. 2020 Dec 15;     [PubMed PMID: 32776781]

[71]

Huber M,Rogozinski S,Puppe W,Framme C,Höglinger G,Hufendiek K,Wegner F, Postinfectious Onset of Myasthenia Gravis in a COVID-19 Patient. Frontiers in neurology. 2020;     [PubMed PMID: 33123081]

[72]

Ortiz-Seller A,Martínez Costa L,Hernández-Pons A,Valls Pascual E,Solves Alemany A,Albert-Fort M, Ophthalmic and Neuro-ophthalmic Manifestations of Coronavirus Disease 2019 (COVID-19). Ocular immunology and inflammation. 2020 Nov 16;     [PubMed PMID: 33021422]

[73]

Ordás CM,Villacieros-Álvarez J,Pastor-Vivas AI,Corrales-Benítez Á, Concurrent tonic pupil and trochlear nerve palsy in COVID-19. Journal of neurovirology. 2020 Dec;     [PubMed PMID: 32910433]

[74]

Kaya Tutar N,Kale N,Tugcu B, Adie-Holmes syndrome associated with COVID-19 infection: A case report. Indian journal of ophthalmology. 2021 Mar;     [PubMed PMID: 33595525]

[75]

Malayala SV,Raza A, A Case of COVID-19-Induced Vestibular Neuritis. Cureus. 2020 Jun 30;     [PubMed PMID: 32760619]

[76]

Wong PF,Craik S,Newman P,Makan A,Srinivasan K,Crawford E,Dev D,Moudgil H,Ahmad N, Lessons of the month 1: A case of rhombencephalitis as a rare complication of acute COVID-19 infection. Clinical medicine (London, England). 2020 May 5;     [PubMed PMID: 32371417]

[77]

Llorente Ayuso L,Torres Rubio P,Beijinho do Rosário RF,Giganto Arroyo ML,Sierra-Hidalgo F, Bickerstaff encephalitis after COVID-19. Journal of neurology. 2020 Sep 3;     [PubMed PMID: 32880723]

[78]

Merkler AE,Parikh NS,Mir S,Gupta A,Kamel H,Lin E,Lantos J,Schenck EJ,Goyal P,Bruce SS,Kahan J,Lansdale KN,LeMoss NM,Murthy SB,Stieg PE,Fink ME,Iadecola C,Segal AZ,Cusick M,Campion TR Jr,Diaz I,Zhang C,Navi BB, Risk of Ischemic Stroke in Patients With Coronavirus Disease 2019 (COVID-19) vs Patients With Influenza. JAMA neurology. 2020 Jul 2;     [PubMed PMID: 32614385]

[79]

Wilkinson SW,Etheridge T,Swiston CJ,Vegunta S,Wiggins RH,Warner JEA, Bilateral Posterior Cerebral Artery Stroke from COVID-Related Multisystem Inflammatory Syndrome in a Child. Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society. 2021 Nov 11;     [PubMed PMID: 34812758]

[80]

Turbin RE,Wawrzusin PJ,Sakla NM,Traba CM,Wong KG,Mirani N,Eloy JA,Nimchinsky EA, Orbital cellulitis, sinusitis and intracranial abnormalities in two adolescents with COVID-19. Orbit (Amsterdam, Netherlands). 2020 Aug     [PubMed PMID: 32419568]

[81]

Shires CB,Klug T,Dryden S,Ford J, Unusual cause of acute sinusitis and orbital abscess in COVID-19 positive patient: Case report. International journal of surgery case reports. 2021 Feb     [PubMed PMID: 33477076]

[82]

Mekonnen ZK,Ashraf DC,Jankowski T,Grob SR,Vagefi MR,Kersten RC,Simko JP,Winn BJ, Acute Invasive Rhino-Orbital Mucormycosis in a Patient With COVID-19-Associated Acute Respiratory Distress Syndrome. Ophthalmic plastic and reconstructive surgery. 2021 Mar-Apr 01     [PubMed PMID: 33229953]

[83]

Mehta S,Pandey A, Rhino-Orbital Mucormycosis Associated With COVID-19. Cureus. 2020 Sep 30     [PubMed PMID: 33145132]

[84]

Sen M,Lahane S,Lahane TP,Parekh R,Honavar SG, Mucor in a Viral Land: A Tale of Two Pathogens. Indian journal of ophthalmology. 2021 Feb;     [PubMed PMID: 33463566]

[85]

Singh AK,Singh R,Joshi SR,Misra A, Mucormycosis in COVID-19: A systematic review of cases reported worldwide and in India. Diabetes     [PubMed PMID: 34192610]

[86]

Werthman-Ehrenreich A, Mucormycosis with orbital compartment syndrome in a patient with COVID-19. The American journal of emergency medicine. 2021 Apr     [PubMed PMID: 32972795]

[87]

Armstrong BK,Murchison AP,Bilyk JR, Suspected orbital myositis associated with COVID-19. Orbit (Amsterdam, Netherlands). 2021 Dec     [PubMed PMID: 34402364]

[88]

Eleiwa T,Abdelrahman SN,ElSheikh RH,Elhusseiny AM, Orbital inflammatory disease associated with COVID-19 infection. Journal of AAPOS : the official publication of the American Association for Pediatric Ophthalmology and Strabismus. 2021 Aug     [PubMed PMID: 33965589]

[89]

Martínez Díaz M,Copete Piqueras S,Blanco Marchite C,Vahdani K, Acute dacryoadenitis in a patient with SARS-CoV-2 infection. Orbit (Amsterdam, Netherlands). 2021 Jan 5     [PubMed PMID: 33402004]

[90]

Pérez-Chimal LG,Cuevas GG,Di-Luciano A,Chamartín P,Amadeo G,Martínez-Castellanos MA, Ophthalmic manifestations associated with SARS-CoV-2 in newborn infants: a preliminary report. Journal of AAPOS : the official publication of the American Association for Pediatric Ophthalmology and Strabismus. 2021 Apr;     [PubMed PMID: 33601042]

[91]

Chen L,Liu M,Zhang Z,Qiao K,Huang T,Chen M,Xin N,Huang Z,Liu L,Zhang G,Wang J, Ocular manifestations of a hospitalised patient with confirmed 2019 novel coronavirus disease. The British journal of ophthalmology. 2020 Jun;     [PubMed PMID: 32265202]

[92]

Amesty MA,Alió Del Barrio JL,Alió JL, COVID-19 Disease and Ophthalmology: An Update. Ophthalmology and therapy. 2020 Sep;     [PubMed PMID: 32445134]

[93]

Varu DM,Rhee MK,Akpek EK,Amescua G,Farid M,Garcia-Ferrer FJ,Lin A,Musch DC,Mah FS,Dunn SP, Conjunctivitis Preferred Practice Pattern®. Ophthalmology. 2019 Jan;     [PubMed PMID: 30366797]

[94]

Seah I,Su X,Lingam G, Revisiting the dangers of the coronavirus in the ophthalmology practice. Eye (London, England). 2020 Feb 6;     [PubMed PMID: 32029919]

[95]

Loon SC,Lun K, SARS: a timely reminder. The British journal of ophthalmology. 2013 Sep;     [PubMed PMID: 23793905]

[96]

Xie X,Li Y,Chwang AT,Ho PL,Seto WH, How far droplets can move in indoor environments--revisiting the Wells evaporation-falling curve. Indoor air. 2007 Jun;     [PubMed PMID: 17542834]

[97]

Wessels IF,Wessels DA,Zimmerman GJ, The photic sneeze reflex and ocular anesthesia. Ophthalmic surgery and lasers. 1999 Mar;     [PubMed PMID: 10100255]

[98]

Morley AM,Jazayeri F,Ali S,Malhotra R, Factors prompting sneezing in intravenously sedated patients receiving local anesthetic injections to the eyelids. Ophthalmology. 2010 May;     [PubMed PMID: 20079540]

[99]

Jun ISY,Hui KKO,Songbo PZ, Perspectives on Coronavirus Disease 2019 Control Measures for Ophthalmology Clinics Based on a Singapore Center Experience. JAMA ophthalmology. 2020 Mar 31;     [PubMed PMID: 32232466]

[100]

Kampf G,Todt D,Pfaender S,Steinmann E, Persistence of coronaviruses on inanimate surfaces and their inactivation with biocidal agents. The Journal of hospital infection. 2020 Mar;     [PubMed PMID: 32035997]