Neuro-Ophthalmic Manifestations of COVID-19

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Article initiated by:
Andrew Go Lee, MD, Malik Ladki, Nagham Al-Zubidi, MD, Noor Laylani, M.D., Pamela Davila-Siliezar, MD
All contributors:
Grace Zhou, Nagham Al-Zubidi, MD, Noor Laylani, M.D., Osama Al Deyabat, MBBS, Mary Labowsky, MD
Assigned editor:
Mary Labowsky, MD
Review:
Assigned status Update Pending
 by Mary Labowsky, MD on October 25, 2023.


Introduction

Infection with the severe acute respiratory syndrome coronavirus (SARS-CoV-2 virus) causes coronavirus disease 2019 (COVID-19), a highly transmissible infection; the first case was reported in Wuhan, China in 2019, followed by rapid world-wide spread and the declaration of a global pandemic in March 2020 by the World Health Organization (WHO). Advancements in the understanding of disease pathogenesis enabled the creation of novel treatments and vaccinations. Although the COVID-19 burden has slowly decreased, many countries remain concerned due to outbreaks of new variants of the disease [1] [2].

COVID-19 usually presents with fever, cough, and shortness of breath, with a range of presentations from asymptomatic to multiorgan failure and death. The infection is not purely a respiratory 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[3].

Epidemiology

To date, COVID-19 has spread to over 223 countries causing over 770 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 [1]. It is responsible for close to 7 million deaths, according to The WHO.[4]

Disease Pathogenesis

The SARS-CoV-2 virus is an enveloped, positive single-strand RNA virus of the coronaviridae family. 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 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.

While 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 [1][5].

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 [5]. The ACE-2 receptor is expressed in neurons and glial cells. The neuro-ophthalmic presentations of COVID-19 may concur with systemic and pulmonary symptoms, or days to weeks after disease resolution [6].

Diagnosis

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 (via nasopharyngeal swabs). The tests identify different regions of the virus’s genome and multiple kits are commercially available. The sensitivity is imperfect 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 [7].

(Systemic) Management

Significant progress in disease management has been made in understanding and management of COVID019, 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% [1].

Neuro-Ophthalmic Manifestations

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[6]

*adapted from Feizi, 2023.
Clinical Entity Clinical Characteristics References
Headache and Ocular Pain Common, may be initial manifestation of COVID-19.

Moderate to severe pulsating/pressing sensation, bilateral, tempor-parietal, forehead or peri orbital regions

Mao L et al, 2020; Chwalisz BK et al, 2020; Huang C et al, 2019
Optic Neuritis Unilateral or bilateral, may be associated with neuromyelitis optica (NMO) spectrum disorders, myelin oligodendrocyte (MOG)-related disease, panuveitis, acute disseminated encephalomyelitis (ADEM). Caudill GB et al, 2020; Benito-Pascual B et al, 2019; Marcos Aet al, 2020; Rodríguez-Rodríguez MS et al, 2021; Deane K et al, 2021; Novi G et al, 2020
Optic Nerve Infarction Vision loss due to internal carotid artery occlusion, optic nerve ischemia revealed on DWI sequence. Tavakoli et al, 2019
Papillophlebitis Decreased visual field sensitivity, dilated and tortuous retinal vessels, disc edema, and retinal hemorrhage; decreased vision due to macular edema. Insausti-García A et al, 2020
Idiopathic Intracranial Hypertension More reported in children than adults due to multisystem inflammatory syndrome (MIS). Verkuil LD et al, 2020; Sofuoğlu AI et al, 2021; Khalid MF et al, 2021
Tonic Adie's Pupil Unilateral or bilateral, associated with multifocal choroiditis; trochlea palsy. Gopal M et al, 2021; Quijano-Nieto BA et al, 2021; Ortiz-Seller A et al, 2020; Kaya Tutar N et al, 2021; Ordás CM et al, 2020
Horner Syndrome Associated with pneumonia involving the upper part of the lung. Popiołek A et al, 2021; Naor MS et al, 2021; Portela-Sánchez S et al, 2021
Visual field defects and Central Visual Impairment Cerebrovascular stroke resulting in homonymous visual field defect, cortical visual blindness, reading difficulties. Tisdale AK et al, 2020; Bondira IP et al, 2021; Cyr DG et al, 2020; Priftis K et al, 2021
Posterior Reversible Encephalopathy Syndrome (PRES) Transient cortical visual loss and hallucinatory palinopsia. Kaya Y et al, 2020; Ghosh R et al, 2020
Cranial Nerve palsy Isolated or multiple cranial nerve involvement including third, fourth, sixth, and seventh. Can occur in the context of Miller Fisher syndrome, Guillain-Barré, myasthenia gravis, venous sinus thrombosis, and increased intracranial pressure. Ordás CM et al, 2020; Douedi S et al, 2021; Cicalese MP et al, 2022; John C et al, 2020; Greer CE et al, 2020; Dinkin M et al, 2020; de Oliveira R de MC et al, 2020; Gutiérrez-Ortiz C et al, 2020; Sansone P et al, 2021; Restivo DA et al, 2020; Mas Maresma L et al, 2020; Lima MA et al, 2020; Juliao Caamaño DS et al, 2020
Nystagmus and abnormal ocular movemement Acquired nystagmus due to acute labyrinthitis, benign paroxysmal positional vertigo, rhombencephalitis, Bickerstaff encephalitis, opsoclonus-myoclonus-ataxia syndrome (OMAS). Perret M et al, 2021; Picciotti PM et al, 2021; Wong P et al, 2022; Llorente Ayuso L et al, 2021; Nelson JL et al, 2022; Emamikhah M et al, 2021
Rhino-orbital-cerebral mucormycosis Mostly occurs in patients receiving high-dose corticosteroid; presented with peri-ocular edema, vision loss, ptosis, and ophthalmo-paresis. Sen M et al, 2021; Pakdel F et al, 2022
Neuroretinitis An acute unilateral visual loss with optic disc swelling and hard exudates arranged in stellate formation around the fovea that can either be infectious or immune-mediated. Coronavirus’ high binding affinity via spike protein S1 for Angiotensin-converting enzyme 2 receptors (ACE2 receptors) could be a less likely mechanism for virus invasion causing neuro-ophthalmic manifestations. May possibly be linked to cytokine storm or systemic abnormalities like hypoxia. Ed-Darraz et al, 2024; Mahajan et, 2022

Headache and Ocular Pain

The 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 [6].

Optic neuritis and Optic Neuropathy

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 [3] [5]. 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 [6].

Diplopia, Cranial Nerve Palsies, and Eye movement disorders

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 [6].

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 [8]. COVID-19-related abducens nerve palsies [9] and unilateral and bilateral trochlear nerve palsies have described in the context of COVID-19 infection [6]. After COVID-19 infection, Miller Fisher syndrome with paresthesia and hyporeflexia was observed [10]. A case study also described the onset of myasthenia gravis in COVID-19 patients with positive cholinergic receptor antibodies [11].

Nystagmus has been described with COVID-19 associated benign paroxysmal positional vertigo, acute labyrinthitis, and encephalitis. Following severe systemic COVID-19 infection, immune-mediated encephalitis can also result in oscillopsia with ataxia and myoclonus [12] or opsoclonus myoclonus ataxia syndrome [13].

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 [14][15]. Children infected with COVID-19 can develop a multisystem inflammatory disease, which can lead to pseudotumor cerebri [16].

Visual Pathways and Visual Field Loss

Infection with COVID-19 increases stroke risk which can cause visual defects if the posterior circulation and visual pathways are affected [17]. There are several cases linking COVID-19 infection with posterior reversible vasoconstriction syndrome (PRES), which can cause patients to develop visual field defects [18]. Hallucinatory palinopsia can also occur in patients with PRES and COVID-19 [19].

Autonomic Pathways

COVID-19 pneumonia involving the upper part of the lung has also been reported to cause Horner’s syndrome [6].

Unilateral or bilateral tonic (Adie) pupil can occur from days to a month following the initial COVID-19 infection. Tonic (Adie) pupil has been associated with COVID-19 infection in one case, also with inflammatory multifocal choroiditis and trochlear nerve palsy, thought to be a result of immune-mediated injury and not direct viral neuronal injury [6].

Secondary Infection

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%) [20].

COVID-19 Vaccine

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 [6]. A sudden surge in acute macular neuroretinopathy (AMN), an acute onset of scotomas caused by ischemia of retinal capillary plexus, can be directly linked to COVID-19 vaccination or infection. COVID-19 can cause thromboses, which would support a possible etiology of AMN, namely causing microvascular ischemia of the choriocapillaris.[21][22][23][24]

Long COVID

“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 [25][26][27].

Management: COVID-19 Related Neuro-Ophthalmic Presentations

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 [5].

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 [28]. 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 [29].

Summary

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.

References

  1. ↑ 1.0 1.1 1.2 1.3 Cascella M, Rajnik M, Cuomo A, Dulebohn SC, Di Napoli R. Features, Evaluation, and Treatment of Coronavirus (COVID-19). StatPearls. 2023 Jan 9; Available from: https://www.ncbi.nlm.nih.gov/books/NBK554776/
  2. ↑ Alfarouk KO, Alhoufie STS, Ahmed SBM, Shabana M, Ahmed A, Alqahtani SS, et al. Pathogenesis and Management of COVID-19. Journal of Xenobiotics 2021, Vol 11, Pages 77-93. 2021 May 21;11(2):77–93. Available from: https://www.mdpi.com/2039-4713/11/2/6/htm
  3. ↑ 3.0 3.1 Gold DM, Galetta SL. Neuro-ophthalmologic complications of coronavirus disease 2019 (COVID-19). Neurosci Lett. 2021 Jan 18;742:135531.
  4. ↑ WHO Coronavirus (COVID-19) Dashboard. https://covid19.who.int. Accessed October 25, 2023
  5. ↑ 5.0 5.1 5.2 5.3 Tisdale AK, Chwalisz BK. Neuro-ophthalmic manifestations of coronavirus disease 19. Curr Opin Ophthalmol. 2020 Nov 1;31(6):489–94. Available from: https://journals.lww.com/co-ophthalmology/Fulltext/2020/11000/Neuro_ophthalmic_manifestations_of_coronavirus.7.aspx
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 6.6 6.7 6.8 Feizi M, Isen DR, Tavakoli M. Neuro-ophthalmic Manifestations of Coronavirus Disease 2019 and Its Vaccination: A Narrative Review. J Ophthalmic Vis Res. 2023 Feb 13 ;18(1):113. Available from: /pmc/articles/PMC10020789/
  7. ↑ Goudouris ES. Laboratory diagnosis of COVID-19. J Pediatr (Rio J). 2021 Jan 1;97(1):7–12.
  8. ↑ Dinkin M, Gao V, Kahan J, Bobker S, Simonetto M, Wechsler P, et al. COVID-19 presenting with ophthalmoparesis from cranial nerve palsy. Neurology. 2020 Aug 4;95(5):221–3. Available from: https://n.neurology.org/content/95/5/221
  9. ↑ Greer CE, Bhatt JM, Oliveira CA, Dinkin MJ. Isolated Cranial Nerve 6 Palsy in 6 Patients With COVID-19 Infection. J Neuroophthalmol. 2020 Dec 1;40(4):520–2. Available from: https://journals.lww.com/jneuro-ophthalmology/Fulltext/2020/12000/Isolated_Cranial_Nerve_6_Palsy_in_6_Patients_With.12.aspx
  10. ↑ Gutiérrez-Ortiz C, Méndez-Guerrero A, Rodrigo-Rey S, San Pedro-Murillo E, Bermejo-Guerrero L, Gordo-Mañas R, et al. Miller Fisher syndrome and polyneuritis cranialis in COVID-19. Neurology. 2020 Aug 4;95(5):e601–5. Available from: https://n.neurology.org/content/95/5/e601
  11. ↑ Restivo DA, Centonze D, Alesina A, Marchese-Ragona R. Myasthenia Gravis Associated With SARS-CoV-2 Infection. https://doi.org/107326/L20-0845. 2020 Aug 10;173(12):1027–8. Available from: https://www.acpjournals.org/doi/10.7326/L20-0845
  12. ↑ Wong PF, Craik S, Newman P, Makan A, Srinivasan K, Crawford E, et al. Lessons of the month 1: A case of rhombencephalitis as a rare complication of acute COVID-19 infection. Clinical Medicine. 2020 May 1;20(3):293–4. Available from: https://www.rcpjournals.org/content/clinmedicine/20/3/293
  13. ↑ Sanguinetti SY, Ramdhani RA. Opsoclonus-Myoclonus-Ataxia Syndrome Related to the Novel Coronavirus (COVID-19). J Neuroophthalmol. 2021 Sep 1;41(3):e288–9. Available from: https://pubmed.ncbi.nlm.nih.gov/32925477/
  14. ↑ Cavalcanti DD, Raz E, Shapiro M, Dehkharghani S, Yaghi S, Lillemoe K, et al. Cerebral Venous Thrombosis Associated with COVID-19. American Journal of Neuroradiology. 2020 Aug 1;41(8):1370–6. Available from: https://www.ajnr.org/content/41/8/1370
  15. ↑ Eliseeva N, Serova N, Yakovlev S, Mikeladze K, Arkhangelskaya Y, Gasparyan S. Neuro-ophthalmological Features of Cerebral Venous Sinus Thrombosis. http://dx.doi.org/103109/016581072014953697. 2015 Apr 1;39(2):69–76. Available from: https://www.tandfonline.com/doi/abs/10.3109/01658107.2014.953697
  16. ↑ Verkuil LD, Liu GT, Brahma VL, Avery RA. Pseudotumor cerebri syndrome associated with MIS-C: a case report. The Lancet. 2020 Aug 22;396(10250):532.
  17. ↑ Beyrouti R, Adams ME, Benjamin L, Cohen H, Farmer SF, Goh YY, et al. Characteristics of ischaemic stroke associated with COVID-19. J Neurol Neurosurg Psychiatry. 2020 Aug 1;91(8):889–91. Available from: https://jnnp.bmj.com/content/91/8/889
  18. ↑ Parauda SC, Gao V, Gewirtz AN, Parikh NS, Merkler AE, Lantos J, et al. Posterior reversible encephalopathy syndrome in patients with COVID-19. J Neurol Sci. 2020 Sep 15;416:117019.
  19. ↑ Ghosh R, Lahiri D, Dubey S, Ray BK, Benito-León J. Hallucinatory Palinopsia in COVID-19-Induced Posterior Reversible Encephalopathy Syndrome. J Neuroophthalmol. 2020 Dec 1;40(4):523–6. Available from: https://journals.lww.com/jneuro-ophthalmology/Fulltext/2020/12000/Hallucinatory_Palinopsia_in_COVID_19_Induced.13.aspx
  20. ↑ Sen M, Honavar S, Sengupta S, Rao R, Kim U, Sharma M, et al. Epidemiology, clinical profile, management, and outcome of COVID-19-associated rhino-orbital-cerebral mucormycosis in 2826 patients in India - Collaborative OPAI-IJO Study on Mucormycosis in COVID-19 (COSMIC), Report 1. Indian J Ophthalmol. 2021 Jul 1 ;69(7):1670–92. Available from: https://pubmed.ncbi.nlm.nih.gov/34156034/
  21. ↑ Dinh, R. H. et al. Acute Macular Neuroretinopathy and Coronavirus Disease 2019. Oph Retina 7, 198–200 (2023).
  22. ↑ Jalink, M. B. & Bronkhorst, I. H. G. A Sudden Rise of Patients with Acute Macular Neuroretinopathy during the COVID-19 Pandemic. Case Rep Ophthalmol 13, 96–103 (2022).
  23. ↑ Vu, T. A., Schillerstrom, M., Mancha, S. & Sponsel, W. E. COVID-19 Related Acute Macular Neuroretinopathy (AMN): A Case Series. Int Med Case Rep J 16, 491–496 (2023).
  24. ↑ Wang, X. et al. Acute macular neuroretinopathy and COVID-19 or SARS-CoV-2 infection: case report and literature review. Front Med (Lausanne) 11, 1267392 (2024).
  25. ↑ Jadali Z, Jalil AT. Long COVID and ophthalmology: New insights into underlying disease mechanisms. Taiwan J Ophthalmol. 2022 Oct 1;12(4):499. Available from: /pmc/articles/PMC9843575/
  26. ↑ Brantl V, Schworm B, Weber G, Schiefelbein J, Kreutzer TC, Michalakis S, et al. Long-term ocular damage after recovery from COVID-19: lack of evidence at three months. BMC Ophthalmol. 2021 Dec 1;21(1):1–6. Available from: https://bmcophthalmol.biomedcentral.com/articles/10.1186/s12886-021-02179-9
  27. ↑ Tana C, Bentivegna E, Cho SJ, Harriott AM, García-Azorín D, Labastida-Ramirez A, et al. Long COVID headache. Journal of Headache and Pain. 2022 Dec 1;23(1):1–12. Available from: https://thejournalofheadacheandpain.biomedcentral.com/articles/10.1186/s10194-022-01450-8
  28. ↑ Martin Paez Y, Bennett JL, Subramanian PS, Pelak VS. Considerations for the Treatment of Inflammatory Neuro-Ophthalmologic Disorders During the COVID-19 Pandemic. Journal of Neuro-Ophthalmology. 2020 Sep 1;40(3):305–14. Available from: /pmc/articles/PMC7418184/
  29. ↑ Stamm B, Huang D, Royan R, Lee J, Marquez J, Desai M. Pathomechanisms and Treatment Implications for Stroke in COVID-19: A Review of the Literature. Life 2022, Vol 12, Page 207 . 2022 Jan 29;12(2):207. Available from: https://www.mdpi.com/2075-1729/12/2/207/htm
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