Ophthalmic Manifestations in COVID-19 infection

Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become pandemic in recent years, and it is still an ongoing concern in global healthcare. The infection ranges from asymptomatic, mild to life-threatening condition, affecting every organ system of the body.

Various manifestations of the eye are also being reported by ophthalmologists. Conjunctivitis is the most common manifestation and can develop at any stage of the disease. The viral RNA has been isolated from the ocular tissues, but the hand-eye contact as the route of transmission is still being debated. The ophthalmic manifestations may be the presenting feature, or they may develop several weeks after recovery.

Ophthalmic manifestations are due to –

1. Direct effect of virus
2. Immune mediated tissue damage
3. Coagulation cascade and prothrombotic state induced by viral infection
4. Associated comorbidities
5. Drugs used in management

COVID-19 infection may involve –

• Eyelid, ocular surface
• Anterior segment of the eye
• Posterior segment of the eye
• Neuro-ophthalmic
• Orbit

Eyelid, Ocular Surface and Anterior Segment Manifestations of COVID-19

Ocular surface manifestations are found in the age range of 24 to 72 years, (mean age -45 years). The gap between COVID-19 diagnosis and ophthalmic findings are found to be around 8.5 days. It may also be the initial or concurrent presentation.

a. Conjunctivitis
It is the most common ophthalmic manifestation in COVID-19 patients. It may be follicular, pseudomembranous or keratoconjunctivitis.
Patient complains redness of one or both eyes, discharge and photophobia. There may be history of hand-eye contact. Risk factors which predispose to ocular surface manifestations are old age, high fever, increased neutrophil/lymphocyte ratio and increased acute phase reactants. Treatment is with lubricants, antibiotic eye drops and/or steroid eye drops (for immune-mediated pathogenesis). Daily debridement of pseudomembrane is needed if present.

b. Episcleritis
Episcleritis presents with foreign body sensation and congestion. Ocular signs may precede symptoms of systemic viral infection. Most cases of episcleritis are self-limiting in nature.

c. Blepharitis
Blepharitis is seen as meibomian orifice abnormalities and lid margin telangiectasia. It may develop as late manifestation of the disease and its incidence is expected to rise in post-pandemic era, especially in patients with pre-existing ocular surface alterations.

Posterior Segment Manifestations of COVID-19

Posterior segment involvement may be vascular, inflammatory and neuronal changes triggered by viral infection. Mean age of the patients is around 47 years. Approximate duration between appearance of ophthalmic symptoms and COVID-19 diagnosis is around 12 days. Many are not associated with systemic comorbidity.

a. Retinal vascular occlusions

1. Central retinal vein occlusion (CRVO)

CRVO may occur in any age but most of the patients are around the age of 50 years. Patient complains decreased vision and fundus examination shows retinal haemorrhages, vascular tortuosity and exudates. Duration between appearance of ophthalmic symptoms and COVID-19 diagnosis is approximately 12 days. Contrary to non-COVID CRVOs, many patients may not have pre-existing hypertension, diabetes or dyslipidemia. There was no correlation between severity of COVID and development of vascular occlusion. However, procoagulant state caused by COVID-19 (elevated D-Dimer, prothrombin time, aPTT, fibrinogen and cytokine) triggers coagulation cascade and predisposes to vascular occlusions. In impending state, high dose steroids may help to normalize coagulation indices. Anti-VEGF is used in the established stage. In patients with systemic comorbidities and severe COVID-19 infection, early anticoagulant prophylaxis should be considered.

2. Central retinal artery occlusion (CRAO)

CRAO presents with sudden onset painless vision loss and it has grave visual prognosis. In such patients, elevated inflammatory markers (IL-6, CRP, ferritin, fibrinogen, D-Dimer) are detected.

3. Acute macular neuroretinopathy (AMN) and Paracentral acute middle maculopathy (PAMM)

These are acute painless decrease in vision due to ischemia in capillary plexuses of retina. Patients with AMN and PAMM are younger than those with CRVO. Management is with topical and tapering doses of oral steroids.

b. Retina

1. Vitritis
   Vitritis may present with redness, blurring of vision and floaters. It is important to rule out other causes of vitritis such as herpes simplex virus, cytomegalo virus, syphilis, toxoplasma, toxocara and inflammatory diseases.
2. Acute retinal necrosis (ARN)
   Patients with acute retinal necrosis complain of floaters and reduced vision. ARN is not common in immunosuppressed states in non-COVID patients. COVID-19 has a role in triggering VZV related ARN by its effect on immune system and by compromising the blood retinal barrier.
3. Others
   COVID patients who are on prophylactic or full intensity anticoagulants to counter the prothrombotic conditions in COVID-19 are prone to have retinal hemorrhages and hard exuates.

c. Uvea

1. Serpiginouschoroiditis
   Reactivation of serpiginouschoroiditis following COVID-19 infection has been reported. Autoimmunity activated by SARS-CoV-2 is believed to play a role in this. Tests for tuberculosis, hepatitis B and C, human immunodeficiency virus, and syphilis should be done to diagnose serpiginous like choroiditis before starting immunomodulatory therapy.

Neuro-ophthalmic Manifestations of COVID-19

Due to neurotropism of the virus, neurologic manifestations like anosmia, headache, dizziness, hypogeusia, Guillain-Barre syndrome and ischemic stroke are frequently seen. Compared with this, neuro-ophthalmic manifestations are relatively uncommon. However isolated case reports are present. Mean age of patients with neuro-ophthalmic manifestations is around 43 years. Patients presented with ophthalmic complaints either concurrently or within a few days of systemic symptoms of COVID-19. The median gap from COVID-19 to development of ophthalmic symptoms is 5 days.

a. Papillophlebitis
Papillophlebitis is uncommon condition. It presents with painless, unilateral, slight diminution of vision. Final visual prognosis is favourable in most cases. Systemic evaluation for hypercoagulable state, vasculitis syndromes and hyperviscosity disorders should be done to determine possible etiology. Association of COVID-19 with coagulopathy and disproportionate inflammatory response or cytokine storm may contribute to the etiology of papillophlebitis.

b. Optic neuritis
Optic neuritis patients present with painful vision loss, relative afferent pupillary defect in more severely affected eye, visual field defects and optic nerve enhancement on magnetic resonance imaging (MRI). Cerebrospinal fluid (CSF) examination, immunological profile, viral panel and imaging of the brain should be done to determine etiology of optic neuritis. Anti-myelin oligodendrocyte glycoprotein antibodies may be present in COVID-19, suggesting parainfectious demyelinating syndrome with viral prodrome. Treatment is the same as that of typical optic neuritis with intravenous methylprednisolone followed by oral prednisolone.

c. Adie’s tonic pupil
Adie’s tonic pupil can result from systemic conditions like diabetes or other viral infections. Complaints like retro-ocular pain and reading difficulty are reported a few days after onset of COVID-19 infection. Short duration suggests direct role of the virus rather than immune mechanisms. Systemic oral steroids lead to full anatomical and functional recovery.

d. Miller Fisher syndrome
Miller fisher syndrome with acute onset ataxia, loss of tendon reflexes and ophthalmoplegia has been reported in patients recently diagnosed with COVID-19. They respond well to intravenous immunoglobulin (IVIG).

e. Cranial nerve palsy
Patients presenting with acute onset diplopia are also seen. Sixth cranial nerve is most common cranial nerve involved, followed by third cranial nerve. It is postulated to be dueto misdirected immune system triggered by viral infection. In most of the cases, spontaneous resolution is seen in 2 to 6 weeks.

f. Neurogenic ptosis
It is also known that COVID-19 infection triggers or exacerbate autoimmune diseases. Patients may present with acute bilateral ptosis and necessary investigations should be carried out to diagnose neurological causes such as Guillain-Barre syndrome (CSF oligoclonal bands) or myasthenia gravis (Acetylcholine receptor antibodies). Patients with rapid worsening of symptoms may require intravenous immunoglobulin therapy.

g. Cerebrovascular accident with vision loss
Procoagulant state combined with pre-existing vascular dysfunction (such as diabetes) predisposes to CVA. Patients presenting with acute bilateral painless vision loss require urgent imaging of the brain with angiography.

Orbital Manifestations of COVID-19

The orbital manifestations can vary from retro-orbital pain to life-threatening invasive mucormycosis. Orbital emphysema is seen as a complication in intubated patients receiving positive end expiratory pressure ventilation. Orbital manifestations are noted in various age groups (12-76 years) with median age of 60 years. Time of presentation from development of COVID-19 symptoms is 12 days. Most of the patients with orbital manifestations are found to have moderate to severe COVID-19. As with other ophthalmic manifestations, direct effect of virus, altered immune status, proinflammatory and hypercoagulable state play their role in pathogenesis.

a.Dacryoadenitis
In healthy young adult, presenting with painful lacrimal gland mass is most commonly dacryoadenitis which is caused by viral infection. If COVID IgG, IgM are positive, and autoimmune, TB and other viral infections have been excluded, diagnosis of dacryoadenitis as late complication of SARS-CoV virus can be made. Acute dacryoadenitis responds well to systemic steroids.

b. Retro-orbital pain
Bilateral retro-orbital pain may be a prominent and presenting symptom in patients with COVID-19 and can mimic conditions like dengue.

c. Orbital cellulitis and sinusitis
Acute onset unilateral, progressive, painful orbital swelling may present in COVID-19 patients with no history of chronic sinus disease. Young patients have a relatively indolent course. However, the superior ophthalmic vein thrombosis may be a thrombotic complication of SARS-CoV-2. In elderly patients with comorbidities, more severe course is seen. Orbital cellulitis may progress to abscess with spreading of infection to adjacent structures. COVID-19 may predispose a patient to infection by bacteria not known to be found in the orbit. Avascular nasal mucosa is also noted, most likely because of thromboembolic complications of COVID-19.

d. Mucormycosis
Mucormycosis is a life-threatening opportunistic infection and patients with moderate to severe COVID-19 are more susceptible to it because of the compromised immune system with decreased CD4+ and CD8+ lymphocytes, associated comorbidities such as diabetes, decompensated pulmonary functions, and use of immunosuppressive therapy (corticosteroids). Rhino-orbital-cerebral mucormycosis can present concurrently with COVID-19 infection. Mortality rate is as high as 50% even with treatment. Almost 70% of rhino-orbital-cerebral mucormycosis is seen in patients with uncontrolled diabetes and most of them have ketoacidosis at the time of presentation. Symptoms of mucormycosis develop as late as 30-42 days after diagnosis of COVID-19. High index of suspicion, early diagnosis with histopathological and microbiological evidence, appropriate management with antifungals and aggressive surgical debridement can improve survival. The signs and symptoms of orbital mucormycosis are not different from those of mucormycosis in non-COVID patients. Simple tests like vision, pupil, ocular motility, and sinus tenderness can be part of routine physical evaluation of COVID-19 patient, hospitalized with moderate to severe infection or diabetics with COVID-19 or those receiving systemic corticosteroids. A nasal swab for KOH and culture is a bedside procedure. Orbital exenteration for life-threatening infection is triaged as an urgent condition requiring surgery within 4-72 hours. Intravenous amphotericin B is started based on clinical suspicion or results of deep nasal swab. MRI is very useful to determine the extent of the disease and intracranial extension.
Patients should be made aware about the risks involved with treatment of COVID-19 and the need for strict glycemic control. Development of unilateral facial or orbital pain, headache, periocular swelling or double vision or decrease in vision should prompt even the COVID-19 recovered patients to seek immediate medical attention. Since majority of the patients developed symptoms of mucormycosis after recovering from COVID-19, follow up of high risk cases is important.

e. Orbital histiocytic lesion
This condition presents with proptosis, eyelid swelling, enlarged lacrimal glands, and lymphadenopathy. Biopsy is needed to confirm to diagnosis.

Discussion

COVID-19 is caused by SARS-CoV-2 virus which belongs to coronaviridae family. It is an enveloped single-stranded RNA virus. It was first reported in Wuhan in China by an ophthalmologist. COVID-19 illness can range from asymptomatic, mild flu-like symptoms to severe respiratory distress. Ophthalmic manifestations are varied in terms of presentation, severity and timing. Ophthalmic manifestations are more common in patients with severe systemic disease with abnormal blood and inflammatory parameters. It has been suggested that exposure of unprotected eyes can lead to infection with the virus. Routes of transmission may be direct inoculation of the conjunctiva by droplets, migration of upper respiratory tract infection through nasolacrimal duct.

References

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Author Information

Khin Ommar Khine¹, Moe Thu Nandy²

1. M.B.,B.S (Ygn), M. Med.Sc (Ophth), FRCS ( Glasgow),
Dr. Med. Sc ( Ophth), Dip. Med. Edu
Clinical Professor Department of Ophthalmology
University of Medicine (1 ) Yangon
2. M. B., B. S (Ygn), M. Med. Sc (Ophth), MRCSEd (Ophth), FICO
Assistant Lecturer, Department of Ophthalmology
University of Medicine (1 ) Yangon