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Review Article|Articles in Press

Neuro-ophthalmic complications of COVID-19 infection and vaccination

Published:March 06, 2023DOI:https://doi.org/10.1016/j.yaoo.2023.03.004
Neuro-ophthalmic complications of COVID-19 infection and vaccination
Previous ArticleInflammatory Choroidal Neovascular Membranes

      Keywords

      Key points:

      • 1.
        COVID-19 infection and vaccination have been associated with neuro-ophthalmic complications, but causation has not been firmly established.
      • 2.
        Neuro-ophthalmic manifestations post-COVID-19 infection and vaccination are
      • uncommon and have a good prognosis in most cases.
      • 3.
        Some of the proposed underlying mechanisms of COVID-19 infection-related neuro-ophthalmic complications are molecular mimicry, direct viral infection, hypoxemia, hypercoagulable status, and hyperviscosity.
      • 4.
        Similarly, the proposed underlying mechanisms of COVID-19 vaccine-related neuro-ophthalmic complications are molecular mimicry, autoimmune syndrome associated with vaccine adjuvant, hypercoagulable status, hyperviscosity, thrombosis, and vasculitis.
      • 5.
        No guidelines are established for the management of neuro-ophthalmic associations post-COVID-19 infection and vaccination in the literature. Therefore, treatment should be tailored to the individual patient and follow established guidelines for the treatment of the clinical phenotype.

      Introduction:

      Severe Acute Respiratory Syndrome caused by corona virus 2 (SARS-CoV-2, COVID-19), is the novel viral infection responsible for the devastating and ongoing COVID-19 pandemic. Since the beginning of the pandemic, the World Health Organization (WHO) estimates over a billion confirmed cases of COVID-19 infection, and over 6 million deaths worldwide have occurred. (

      World Health Organization. (2020). Novel Coronavirus (2019-nCoV): situation report, 11. World Health Organization. [Internet]. [cited 2022 May 20]. Available from: https://apps.who.int/iris/handle/10665/330776

      ) This devastating disease has had implications for all aspects of medicine with new disease phenotypes emerging, including in ophthalmology.
      The scale of this pandemic has led to an unprecedented rapid creation of vaccines against COVID-19. Since becoming available to the public at the end of 2020, over 12 billion COVID-19 vaccine doses have been administered worldwide. This has led to a marked reduction in the rate of infections, transmissions, hospitalizations, and death from COVID-19 infection and, hopefully, will lead to the end of this pandemic. (
      • Ranzani OT
      • Hitchings MDT
      • Dorion M
      • D’Agostini TL
      • de Paula RC
      • de Paula OFP
      • et al.
      Effectiveness of the CoronaVac vaccine in older adults during a gamma variant associated epidemic of covid-19 in Brazil: Test negative case-control study.
      The BMJ. 2021 Aug 20; : 374
      ,
      • Chung H
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      Effectiveness of BNT162b2 and mRNA-1273 covid-19 vaccines against symptomatic SARS-CoV-2 infection and severe covid-19 outcomes in Ontario, Canada: Test negative design study.
      The BMJ. 2021 Aug 20; : 374
      ,

      Bernal JL, Andrews N, Gower C, Robertson C, Stowe J, Tessier E, et al. Effectiveness of the Pfizer-BioNTech and Oxford-AstraZeneca vaccines on covid-19 related symptoms, hospital admissions, and mortality in older adults in England: test negative case-control study. BMJ [Internet]. 2021 May 13 [cited 2022 Sep 27];373. Available from: https://www.bmj.com/content/373/bmj.n1088

      ) However, new presentations of autoimmune conditions have been associated with COVID-19 vaccination. (
      • Netravathi M
      • Dhamija K
      • Gupta M
      • Tamborska A
      • Nalini A
      • Holla V v.
      • et al.
      COVID-19 vaccine associated demyelination & its association with MOG antibody.
      Mult Scler Relat Disord. 2022 Apr 1; : 60
      )The post-infection and post-vaccine manifestations of the COVID-19 pandemic are still emerging. Reports have demonstrated that SARS-CoV-2 infection and vaccination can affect multiple organ systems including the eyes, resulting in a spectrum of ocular manifestations such as conjunctivitis, episcleritis, uveitis, vascular occlusions, and retinitis. Also, neuro-ophthalmic manifestations exist, ranging from a simple headache to irreversible blindness from optic neuritis (ON) or giant cell arteritis (GCA).
      Some of these new vaccines use novel technology and long-term data on potential side effects is still pending. The WHO recommendation for reporting possible vaccine side effects is the presence of a temporal association between the administration of the vaccine and the onset of symptoms, with a suggested cut off of 28 days between vaccination and symptoms. The exclusion exists of other triggers for the disease manifestation and the presence of published literature with an established possible relationship between the vaccination and disease onset or exacerbation. (

      World Health Organization. COVID-19 Vaccines :Safety Surveillance Manual Module : Responding to Adverse Events. Geneva: World Health Organization; 2020.

      )
      This review aims to focus on, and summarize, the current state of knowledge of neuro-ophthalmic complications of COVID-19 infection and vaccination.

      Methodology

      The EMBASE, Ovid MEDLINE, and Cochrane central library were searched by a medical librarian from January 1, 2019, until September 28, 2022, using keywords to cover ocular and neuro-ophthalmological complications of COVID-19 infection and vaccination. Manual selection was used to identify articles of interest. The search was restricted to English language.

      Discussion

      Afferent neuro-ophthalmic complications:

      Optic neuritis

      Post COVID-19 infection:

      Generally, most cases of optic neuritis (ON) associated with COVID-19 infection have a remarkable improvement in vision after treatment with steroids, with only a few reported cases of irreversible vision loss. (

      Jossy A, Jacob N, Sarkar S, Gokhale T, Kaliaperumal S, Deb A. COVID-19-associated optic neuritis - A case series and review of literature. Vol. 70, Indian Journal of Ophthalmology. Wolters Kluwer Medknow Publications; 2022. p. 310–316.

      ,
      • Mabrouki FZ
      • Sekhsoukh R
      • Aziouaz F
      • Mebrouk Y
      Acute Blindness as a Complication of Severe Acute Respiratory Syndrome Coronavirus-2.
      Cureus. 2021 Aug 3;
      ) Most of the cases were unilateral with variable onset ranging between (1 to 45 days) post-infection.(
      • Rojas-Correa DX
      • Reche-Sainz JA
      • Insausti-García A
      • Calleja-García C
      • Ferro-Osuna M
      Post COVID-19 Myelin Oligodendrocyte Glycoprotein Antibody-Associated Optic Neuritis.
      Neuro-Ophthalmology. 2021;
      ,
      • Rodríguez-Rodríguez MS
      • Romero-Castro RM
      • Alvarado-de la Barrera C
      • González-Cannata MG
      • García-Morales AK
      • Ávila-Ríos S
      Optic neuritis following SARS-CoV-2 infection.
      J Neurovirol. 2021 Apr 1; 27: 359-363
      ,
      • Assavapongpaiboon B
      • Apinyawasisuk S
      • Jariyakosol S
      Myelin oligodendrocyte glycoprotein antibody-associated optic neuritis with COVID-19 infection: A case report and literature review.
      Am J Ophthalmol Case Rep. 2022 Jun 1; : 26
      ) All cases received 1g/day of intravenous methylprednisolone (IVMP) followed by oral prednisone taper. (

      Jossy A, Jacob N, Sarkar S, Gokhale T, Kaliaperumal S, Deb A. COVID-19-associated optic neuritis - A case series and review of literature. Vol. 70, Indian Journal of Ophthalmology. Wolters Kluwer Medknow Publications; 2022. p. 310–316.

      ) Additionally, myelin oligodendrocyte glycoprotein (MOG)-related optic neuritis was found to have a favorable visual outcome following IVMP with vision better than 20/200 in all cases.(
      • Assavapongpaiboon B
      • Apinyawasisuk S
      • Jariyakosol S
      Myelin oligodendrocyte glycoprotein antibody-associated optic neuritis with COVID-19 infection: A case report and literature review.
      Am J Ophthalmol Case Rep. 2022 Jun 1; : 26
      ) In a systematic review, only 3 cases of neuro-myelitis optica (NMO) Aquaporin 4 IgG positive ON were identified. (

      Mirmosayyeb O, Ghaffary EM, Bagherieh S, Barzegar M, Dehghan MS, Shaygannejad V. Post COVID-19 infection neuromyelitis optica spectrum disorder (NMOSD): A case report-based systematic review. Vol. 60, Multiple Sclerosis and Related Disorders. Elsevier B.V.; 2022.

      ) Two were men, 70 and 25 years old, and one in a 7.5 years-old girl. They all presented within a month of their COVID-19 infection. Treatment with steroids, IVIG, PLEX, and rituximab were administered, and gradual improvement was observed in 2 of the patients. Whereas the 70-year-old was treated only with antibiotics, fluids and electrolytes, and eventually the patient died from systemic complications of COVID-19. (

      Mirmosayyeb O, Ghaffary EM, Bagherieh S, Barzegar M, Dehghan MS, Shaygannejad V. Post COVID-19 infection neuromyelitis optica spectrum disorder (NMOSD): A case report-based systematic review. Vol. 60, Multiple Sclerosis and Related Disorders. Elsevier B.V.; 2022.

      )

      Post COVID-19 vaccination:

      Optic neuritis post-covid-19 vaccination is the most common reported neuro-ophthalmic association, (

      Martinez-Alvarez L, Ning Neo Y, Davagnanam BMedSci FRCR I, Ashenhurst M, Acheson J, Frcs Frco, et al. Title suggestion: Post vaccination optic neuritis: observations from the SARS-CoV-2 pandemic [Internet]. Available from: https://ssrn.com/abstract=3889990

      ) with fifty-five individual case reports published in the literature. Of these two thirds were vaccinated with the Oxford/AstraZeneca ChAdOx1, followed by BioNTech/Pfizer mRNA-vaccine BNT162b2 vaccine (26%) and Sinovac (7%). The onset of vision loss was with-in three weeks from the administration of the vaccine in most patients. This is one week after the antibodies from the vaccine are thought to be formed, which occurs on average at 2 weeks. Most cases were reported in Caucasians (44/55) women (38/55) with a median age of 45 years, which is higher than the typical cases of pre-pandemic ON. Unilateral involvement was more common than bilateral. MOG positive ON were reported in 14 cases, followed by 7 cases of multiple sclerosis (MS) associated ON. This contrasts with the existing literature where MS-ON accounts for the majority (57%) of cases. (
      • Hassan MB
      • Stern C
      • Flanagan EP
      • Pittock SJ
      • Kunchok A
      • Foster RC
      • et al.
      Population-Based Incidence of Optic Neuritis in the Era of Aquaporin-4 and Myelin Oligodendrocyte Glycoprotein Antibodies.
      Am J Ophthalmol. 2020 Dec 1; 220: 110-114
      ,

      Chen JJ, Pittock SJ, Flanagan EP, Lennon VA, Bhatti MT. Optic neuritis in the era of biomarkers. Vol. 65, Survey of Ophthalmology. Elsevier USA; 2020. p. 12–17.

      ) Unlike, typical ON almost half of the patients presented with optic disc swelling (27/55). The treatment of choice was high-dose intravenous steroids in most cases, and a few cases received high doses of oral steroids, while 7 cases did not receive any steroids. Plasma exchange (PLEX) was used in 6 cases either with or after the course of steroids. Median vision after treatment was 20/20. However, 5 cases occurred with vision worse than 20/200.
      In a separate study of fourteen cases of idiopathic ON post-COVID-19 vaccination (

      Leber HM, Sant’Ana L, Konichi da Silva NR, Raio MC, Mazzeo TJMM, Endo CM, et al. Acute Thyroiditis and Bilateral Optic Neuritis following SARS-CoV-2 Vaccination with CoronaVac: A Case Report. Vol. 29, Ocular Immunology and Inflammation. Taylor and Francis Ltd.; 2021. p. 1200–6.

      ,
      • Roy M
      • Chandra A
      • Roy S
      • Shrotriya C
      Optic neuritis following COVID-19 vaccination: Coincidence or side-effect? - A case series.
      Indian J Ophthalmol. 2022 Feb 1; 70: 679-683
      ,
      • Assiri SA
      • Althaqafi RMM
      • Alswat K
      • Alghamdi AA
      • Alomairi NE
      • Nemenqani DM
      • et al.
      Post COVID-19 Vaccination-Associated Neurological Complications.
      Neuropsychiatr Dis Treat. 2022; 18: 137-154
      ,

      Arnao V, Maimone MB, Perini V, Giudice G lo, Cottone S. Bilateral optic neuritis after COVID vaccination. Vol. 43, Neurological Sciences. Springer-Verlag Italia s.r.l.; 2022. p. 2965–2966.

      ,
      • Elnahry AG
      • Asal ZB
      • Shaikh N
      • Dennett K
      • Abd Elmohsen MN
      • Elnahry GA
      • et al.
      Optic neuropathy after COVID-19 vaccination: a report of two cases.
      International Journal of Neuroscience. 2021;
      ,
      • Katayama H
      • Itoh K
      • Hashimoto M
      Bilateral Optic Neuritis after COVID-19 mRNA Vaccination.
      Case Rep Ophthalmol. 2022 Aug 5; 13: 578-583
      ,
      • García-Estrada C
      • Gómez-Figueroa E
      • Alban L
      • Arias-Cárdenas A
      Optic neuritis after COVID-19 vaccine application.
      Clin Exp Neuroimmunol. 2022 May 1; 13: 72-74
      ,

      Bhatti MT, Gilbert AL, Watson G, Waheed M, Spencer D. Shot in the dark. Surv Ophthalmol [Internet]. 2022 Sep; Available from: https://linkinghub.elsevier.com/retrieve/pii/S0039625722001230

      ) again, most cases were in women (10 cases) half with unilateral involvement, and age ranged from 19- 67 years. Vision changes were reported from hours to 3 weeks after BioNTech/Pfizer mRNA-vaccine BNT162b2, AstraZeneca ChAdOx1, Janssen (Johnson & Johnson), Covisheild, CoronaVac-Sinovac Life, and Moderna mRNA-1273 vaccines. Optic disc swelling was noted in 8 cases on examination, and the presenting visual acuity of < 20/200 was noted in 4 cases. Universally there appears to be a good visual prognosis after receiving steroids. PLEX for 7 days was given only to 1 patient who failed to improve on IVMP, and had a vision of counting fingers in both eyes. (

      Bhatti MT, Gilbert AL, Watson G, Waheed M, Spencer D. Shot in the dark. Surv Ophthalmol [Internet]. 2022 Sep; Available from: https://linkinghub.elsevier.com/retrieve/pii/S0039625722001230

      )
      MOG-ON was reported to comprise approximately 5% of ON cases pre-pandemic, (

      Chen JJ, Pittock SJ, Flanagan EP, Lennon VA, Bhatti MT. Optic neuritis in the era of biomarkers. Vol. 65, Survey of Ophthalmology. Elsevier USA; 2020. p. 12–17.

      ) with an increased rate of MOG-ON since the start of the pandemic.(
      • Netravathi M
      • Dhamija K
      • Gupta M
      • Tamborska A
      • Nalini A
      • Holla V v.
      • et al.
      COVID-19 vaccine associated demyelination & its association with MOG antibody.
      Mult Scler Relat Disord. 2022 Apr 1; : 60
      ,

      Martinez-Alvarez L, Ning Neo Y, Davagnanam BMedSci FRCR I, Ashenhurst M, Acheson J, Frcs Frco, et al. Title suggestion: Post vaccination optic neuritis: observations from the SARS-CoV-2 pandemic [Internet]. Available from: https://ssrn.com/abstract=3889990

      ,

      Badeeb N, Torres C, Albreiki D. Case of Bilateral Optic Neuritis With Positive Myelin Oligodendrocyte Glycoprotein Antibody Testing Post-COVID-19 Vaccination. J Neuroophthalmol [Internet]. 2022 Apr 28; Available from: http://journals.lww.com/jneuro-ophthalmology

      ,
      • Donaldson LC
      • Margolin EA
      Myelin Oligodendrocyte Glycoprotein Antibody-Mediated Optic Neuritis Following COVID-19 Vaccination.
      J Neuroophthalmol. 2022 Feb 28;
      ,
      • Wang J
      • Huang S
      • Yu Z
      • Zhang S
      • Hou G
      • Xu S
      Unilateral optic neuritis after vaccination against the coronavirus disease: two case reports.
      Documenta Ophthalmologica. 2022 Aug 1; 145: 65-70
      ,

      Morena J, Gyang T v. Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease and Transverse Myelitis Probably Associated With SARS-CoV-2 mRNA Vaccines: Two Case Reports. Neurohospitalist. 2022 Jul 1;12(3):536–540.

      ) There are 10 case reports of post-COVID-19 vaccine associated MOG-ON in the literature. Most have been in men (7 cases) between the ages 28-66 years with most (7 cases) having unilateral involvement. Half had a visual acuity of <20/200 at presentation and the onset of vision loss was reported between 14 and 21 days and after the AstraZeneca ChAdOx1 vaccine. The treatment of choice was IVMP for 3-5 days, followed by oral steroids. In 4 cases, presenting with poor vision or bilateral involvement, PLEX was initiated. Only one case had a spontaneous resolution of vision with no intervention.
      NMO-ON was reported in (3%) of patients pre-pandemic, and it remained an uncommon cause of ON post-vaccination. (

      Chen JJ, Pittock SJ, Flanagan EP, Lennon VA, Bhatti MT. Optic neuritis in the era of biomarkers. Vol. 65, Survey of Ophthalmology. Elsevier USA; 2020. p. 12–17.

      ) Case reports of NMO-ON post-vaccination exists and include cases after mRNA vaccination. A 43-year-old and 31-year-old woman, both with unilateral involvement, one with complete recovery of her vision after receiving IVMP 1g/d for 10 days, and the other with no visual recovery after receiving IVMP (1g/d) for 5 days followed by 5 sessions of PLEX. (
      • Caliskan I
      • Bulus E
      • Afsar N
      • Altintas A
      A Case With New-onset Neuromyelitis Optica Spectrum Disorder Following COVID-19 mRNA BNT162b2 Vaccination.
      Neurologist. 2022;
      ,

      Shirah B, Mulla I, Aladdin Y. Optic Neuritis Following the BNT162b2 mRNA COVID-19 Vaccine in a Patient with Systemic Lupus Erythematosus Uncovering the Diagnosis of Neuromyelitis Optica Spectrum Disorders. Ocular Immunology and Inflammation. Taylor and Francis Ltd.; 2022.

      )

      Giant cell arteritis

      Post COVID-19 infection:

      A noticeable increase in giant cell arteritis (GCA) cases occurred during the COVID-19 pandemic, a report by Lecler et al, observed an increase of 70% from pre-pandemic. (
      • Lecler A
      • Villeneuve D
      • Vignal C
      • Sené T
      Increased rather than decreased incidence of giant-cell arteritis during the COVID-19 pandemic.
      Ann Rheum Dis. 2021; 80: e89
      ) Subsequently, higher rates of ocular involvement were seen with GCA during the pandemic. (
      • Szydełko-Paśko U
      • Przeździecka-Dołyk J
      • Kręcicka J
      • Małecki R
      • Misiuk-Hojło M
      • Turno-Kręcicka A
      Arteritic Anterior Ischemic Optic Neuropathy in the Course of Giant Cell Arteritis After COVID-19.
      American Journal of Case Reports. 2022; 23
      ,
      • Luther R
      • Skeoch S
      • Pauling JD
      • Curd C
      • Woodgate F
      • Tansley S
      Increased number of cases of giant cell arteritis and higher rates of ophthalmic involvement during the era of COVID-19.
      Rheumatol Adv Pract. 2021; 4
      ) This supports the notion of the role of viral infections as an underlying trigger for GCA. In the era of the pandemic, diagnosing GCA is challenging due to the similarities between COVID-19 infection manifestations and GCA. A study by Mehta et al, found that they both share the clinical features of headache, fever, elevated CRP, and cough. Clinical manifestations that can aid in the differentiation of GCA would be jaw claudication, visual loss, platelet count, and lymphocyte count. (

      Mehta Puja Kornelis, Sattui Sebastian, S M van der Geest, Brouwer E, Conway R, Putman MS, et al. Giant Cell Arteritis and COVID-19: Similarities and Discriminators. A Systematic Literature Review. J Rheumatol. 2021 Jul;48(7):1053–1059.

      )

      Post COVID-19 vaccination:

      Three case reports exist of GCA presenting with arteritic anterior ischemic optic neuropathy (AAION) after COVID-19 vaccination. (
      • Maleki A
      • Look-Why S
      • Manhapra A
      • Foster CS
      COVID-19 recombinant mRNA vaccines and serious ocular inflammatory side effects: Real or coincidence?.
      J Ophthalmic Vis Res. 2021; 16: 490-501
      ,
      • Xia C
      • Edwards R
      • Omidvar B
      A Case of Giant Cell Arteritis With a Normal Erythrocyte Sedimentation Rate (ESR) Post ChAdOx1 nCoV-19 Vaccination.
      Cureus. 2022 May 27;
      ,
      • Che SA
      • Lee Y
      • Yoo YJ
      Bilateral Ischemic Optic Neuropathy From Giant Cell Arteritis Following COVID-19 Vaccination.
      J Neuroophthalmol. 2022 Jun 14;
      ) Two in 87 and 79-year-old women, and one in a 68-year-old man. Two cases were after BioNTech/Pfizer mRNA-vaccine BNT162b2 vaccine and one after the AstraZeneca ChAdOx1 vaccine. They all presented within 5 days of receiving the vaccine and all had bilateral involvement. The visual acuity was <20/200 in at least one eye at the time of the presentation. Some had other symptoms of GCA including amaurosis fugax, headache, jaw claudication, scalp tenderness, and lethargy. At least one of the inflammatory markers was high, ESR in 2 cases and C-reactive protein (CRP) in all three cases. A temporal artery biopsy was positive in two of the patients, and for one patient no information was provided about the biopsy. All cases were treated with high-dose IVMP (1g/d x 3-4 days) followed by oral prednisolone (
      • Maleki A
      • Look-Why S
      • Manhapra A
      • Foster CS
      COVID-19 recombinant mRNA vaccines and serious ocular inflammatory side effects: Real or coincidence?.
      J Ophthalmic Vis Res. 2021; 16: 490-501
      ,
      • Xia C
      • Edwards R
      • Omidvar B
      A Case of Giant Cell Arteritis With a Normal Erythrocyte Sedimentation Rate (ESR) Post ChAdOx1 nCoV-19 Vaccination.
      Cureus. 2022 May 27;
      ,
      • Che SA
      • Lee Y
      • Yoo YJ
      Bilateral Ischemic Optic Neuropathy From Giant Cell Arteritis Following COVID-19 Vaccination.
      J Neuroophthalmol. 2022 Jun 14;
      ), one patient subsequently received tocilizumab (TCZ) following a relapse 3 months after initial presentation. (
      • Maleki A
      • Look-Why S
      • Manhapra A
      • Foster CS
      COVID-19 recombinant mRNA vaccines and serious ocular inflammatory side effects: Real or coincidence?.
      J Ophthalmic Vis Res. 2021; 16: 490-501
      )
      In both post-COVID and post-vaccination cases no proved causation exists and the time lapse for the post-vaccination cases theoretically is too soon for the body to have mounted an immune response. Given the number of vaccinations administered to date, some overlap with GCA would be expected.

      Non-Arteritic Anterior Ischemic Optic Neuropathy (NA-AION)

      Post COVID-19 infection:

      The relationship of COVID-19 and NA-AION is unknown. (
      • Clarke KM
      • Riga V
      • lee Shirodkar A
      • Meyer J
      Proning related bilateral anterior ischaemic optic neuropathy in a patient with COVID-19 related acute respiratory distress syndrome.
      BMC Ophthalmol. 2021 Dec 1; : 21
      ) NA-AION has been described in six case reports in association with COVID-19 infection. (
      • Yüksel B
      • Bıçak F
      • Gümüş F
      • Küsbeci T
      Non-Arteritic Anterior Ischaemic Optic Neuropathy with Progressive Macular Ganglion Cell Atrophy due to COVID-19.
      Neuro-Ophthalmology. 2022; 46: 104-108
      ,
      • Sanoria A
      • Jain P
      • Arora R
      • Bharti N
      Bilateral sequential non-arteritic optic neuropathy post-COVID-19.
      Indian J Ophthalmol. 2022 Feb 1; 70: 676-679
      ,
      • Sitaula S
      • Poudel A
      • Gajurel BP
      Non-arteritic anterior ischemic optic neuropathy in COVID-19 infection – A case report.
      Am J Ophthalmol Case Rep. 2022 Sep 1; : 27
      ,

      Babazadeh A, Barary M, Ebrahimpour S, Sio TT, Mohseni Afshar Z. Non-arteritic anterior ischemic optic neuropathy as an atypical feature of COVID-19: A case report. Vol. 45, Journal Francais d’Ophtalmologie. Elsevier Masson s.r.l.; 2022. p. e171–3.

      ,

      Rho J, Dryden SC, McGuffey CD, Fowler BT, Fleming J. A Case of Non-Arteritic Anterior Ischemic Optic Neuropathy with COVID-19. Cureus. 2020 Dec 7;

      ) Patients in these reports were above 40 years old and presented with acute painless unilateral or bilateral (2/6) altitudinal vision loss, which mainly was noted upon awakening (4/6 patients). The onset of visual symptoms ranged from one to four weeks after COVID-19 infection except in one patient where visual symptoms preceded COVID-19 symptoms. (

      Babazadeh A, Barary M, Ebrahimpour S, Sio TT, Mohseni Afshar Z. Non-arteritic anterior ischemic optic neuropathy as an atypical feature of COVID-19: A case report. Vol. 45, Journal Francais d’Ophtalmologie. Elsevier Masson s.r.l.; 2022. p. e171–3.

      ) All cases demonstrated visual field defect on confrontational testing and Humphrey’s visual field analysis. (
      • Yüksel B
      • Bıçak F
      • Gümüş F
      • Küsbeci T
      Non-Arteritic Anterior Ischaemic Optic Neuropathy with Progressive Macular Ganglion Cell Atrophy due to COVID-19.
      Neuro-Ophthalmology. 2022; 46: 104-108
      ,
      • Sanoria A
      • Jain P
      • Arora R
      • Bharti N
      Bilateral sequential non-arteritic optic neuropathy post-COVID-19.
      Indian J Ophthalmol. 2022 Feb 1; 70: 676-679
      )

      Post COVID-19 vaccination:

      NA-AION post-COVID-19 vaccination has rarely been reported. (
      • Lin WY
      • Wang JJ
      • Lai CH
      Non‐Arteritic Anterior Ischemic Optic Neuropathy Following COVID‐19 Vaccination.
      Vaccines (Basel). 2022 Jun 1; 10
      ,

      Tsukii R, Kasuya Y, Makino S. Nonarteritic Anterior Ischemic Optic Neuropathy following COVID-19 Vaccination: Consequence or Coincidence. Case Rep Ophthalmol Med. 2021 Oct 14;2021:1–4.

      ,
      • Franco SV
      • Fonollosa A
      Ischemic Optic Neuropathy After Administration of a SARS-CoV-2 Vaccine: A Report of 2 Cases.
      American Journal of Case Reports. 2022; 23
      ,

      Elhusseiny AM, Sanders RN, Siddiqui MZ, Sallam AB. Non-arteritic Anterior Ischemic Optic Neuropathy with Macular Star following COVID-19 Vaccination. Vol. 30, Ocular Immunology and Inflammation. Taylor and Francis Ltd.; 2022. p. 1274–1277.

      ,

      Chung SA, Yeo S, Sohn SY. Nonarteritic Anterior Ischemic Optic Neuropathy Following COVID-19 Vaccination: A Case Report. Vol. 36, Korean Journal of Ophthalmology. Korean Ophthalmological Society (KOS); 2022. p. 168–170.

      ,

      Nachbor KM, Naravane A v, Adams OE, Abel AS. Nonarteritic Anterior Ischemic Optic Neuropathy Associated With COVID-19 Vaccination [Internet]. Available from: http://links.lww.com/WNO/A525

      ) All patients shared the clinical presentation of painless sudden vision changes either described as a blurring of vision or a visual field defect and all had unilateral involvement. The onset of visual symptoms was with-in 15 days from the vaccination, (1-15 days). Most of the patients were older than 50 and had one or more risk factors for developing NAION; small cup-to-disc ratio, hypertension, diabetes or dyslipidemia.
      Some of the cases underwent investigations to rule out GCA, along with brain and orbit imaging to rule out optic neuritis. IV or PO steroids were administered in some cases, either for the suspicion of optic neuritis or giant cell arteritis. Some tried steroids as an intervention when the visual acuity was poor as a treatment of last resort to improve vision, and it was deemed successful in 1 case where vision improved from count fingers (CF) to 20/100-1 eccentrically after 6 weeks. (

      Nachbor KM, Naravane A v, Adams OE, Abel AS. Nonarteritic Anterior Ischemic Optic Neuropathy Associated With COVID-19 Vaccination [Internet]. Available from: http://links.lww.com/WNO/A525

      ) This case report doesn’t demonstrate causation or bestow a treatment effect from steroids as up to a third of NAION cases will report some improvement in vision, especially once the disc edema resolves.

      Papilledema

      Post COVID-19 infection:

      Headache is a prominent symptom of both elevated intracranial pressure (ICP) and COVID-19. In a cross-sectional study of 56 patients with COVID-19 infection 13 had a new persistent headache prompting further clinical evaluation including lumbar puncture. (
      • Silva MTT
      • Lima MA
      • Torezani G
      • Soares CN
      • Dantas C
      • Brandão CO
      • et al.
      Isolated intracranial hypertension associated with COVID-19.
      Cephalalgia. 2020 Nov 1; 40: 1452-1458
      ) Of those 85% (11/13) were found to have high opening pressure (> 200mmH2O), and over half (7/13) were above (250mmH2O) with normal composition and were diagnosed with IIH. Imaging of the brain was not significant except in one patient who had typical imaging features of increased intracranial pressure. All patients had normal fundoscopic examinations except for 2 who showed papilledema. Interestingly, blurred vision was reported by only three patients.
      Cerebral venous sinus thrombosis is a serious complication post COVID-19 infection. Nearly all reported cases of papilledema related to CVST in the setting of COVID-19 had a favorable visual outcome except the case described by Omari et al. of a morbidly obese woman who presented with a bilateral progressive visual loss associated with severe headache and tinnitus. The patient recently was admitted to the hospital for bilateral pulmonary embolism and deep venous thrombosis, possibly due to COVID-19 infection. (
      • Omari A
      • Kally P
      • Schimmel O
      • Kahana A
      Vision Loss Secondary to COVID-19 Associated Bilateral Cerebral Venous Sinus Thromboses.
      Ophthalmic Plast Reconstr Surg. 2022 May 15; 38: e65-e67
      ) CSF workup was remarkable only for an elevated opening pressure of more than (600 mmH2O). Despite maximum treatment, with acetazolamide and heparin, bilateral optic nerve sheath fenestration (ONSF), and endovascular transverse sinus thrombectomy, her vision deteriorated to no light perception (NLP).

      Post COVID-19 vaccination:

      There have been 2 published case reports of papilledema in the setting of COVID-19 vaccination-associated IIH. (
      • Farahani AA
      • Shahali H
      Intracranial Hypertension and Papilledema: An Unusual Complication After the Adenoviral DNA Vector–Based Coronavirus Disease 2019 Vaccination in an Air Medical Transportation Pilot.
      Air Med J. 2022;
      ,
      • Thunstedt DC
      • Straube A
      • Schöberl F
      Isolated intracranial hypertension following COVID-19 vaccination: A case report.
      Cephalalgia Rep. 2021; : 4
      ) Both cases were young male patients with normal body mass index (BMI) and atypical demographics for IIH. One presented 7 days after the AstraZeneca ChAdOx1 vaccine, and the other 12 days after Sputnik V vaccine. Both had other symptoms of high ICP such as headache, pulsatile tinnitus, dizziness and blurring of vision. MRI/MRV were normal except for signs of high ICP. Lumbar puncture with high opening pressure of (620mmH2O and 390mmH2O). One was treated with acetazolamide 750mg twice daily and torsemide 5mg once daily, and the other was given pulse IVMP 500mg daily for 5 days and oral acetazolamide 250mg three times a day. After three months the symptoms and papilledema had completely resolved in both cases. (
      • Farahani AA
      • Shahali H
      Intracranial Hypertension and Papilledema: An Unusual Complication After the Adenoviral DNA Vector–Based Coronavirus Disease 2019 Vaccination in an Air Medical Transportation Pilot.
      Air Med J. 2022;
      ,
      • Thunstedt DC
      • Straube A
      • Schöberl F
      Isolated intracranial hypertension following COVID-19 vaccination: A case report.
      Cephalalgia Rep. 2021; : 4
      )
      The above-mentioned cases did not involve CVST. However, coagulation problems that result in CVST have been reported post-COVID-19 vaccination, presenting with intracranial hypertension and papilledema. Other associated symptoms are headache, focal neurological deficit, seizures, and venous hemorrhage. Symptoms appear to happen approximately (10 days) from the day of the vaccination. Most cases were reported with the AstraZeneca ChAdOx1 vaccine. (
      • Jaiswal V
      • Nepal G
      • Dijamco P
      • Ishak A
      • Dagar M
      • Sarfraz Z
      • et al.
      Cerebral Venous Sinus Thrombosis Following COVID-19 Vaccination: A Systematic Review.
      J Prim Care Community Health. 2022 Feb 1; : 13
      ,
      • Matar RH
      • Than CA
      • Nakanishi H
      • Daniel RS
      • Smayra K
      • Sim BL
      • et al.
      Outcomes of patients with thromboembolic events following coronavirus disease 2019 AstraZeneca vaccination: a systematic review and meta-analysis.
      Blood Coagul Fibrinolysis. 2022 Mar 1; 33: 90-112
      ) The group most at risk was women under 60 years of age. (
      • Matar RH
      • Than CA
      • Nakanishi H
      • Daniel RS
      • Smayra K
      • Sim BL
      • et al.
      Outcomes of patients with thromboembolic events following coronavirus disease 2019 AstraZeneca vaccination: a systematic review and meta-analysis.
      Blood Coagul Fibrinolysis. 2022 Mar 1; 33: 90-112
      ) It is thought that CVST post-COVID-19 vaccine is secondary to vaccine-induced thrombotic thrombocytopenia (VITT), which is similar to heparin-induced thrombocytopenia (HIT). (
      • Jaiswal V
      • Nepal G
      • Dijamco P
      • Ishak A
      • Dagar M
      • Sarfraz Z
      • et al.
      Cerebral Venous Sinus Thrombosis Following COVID-19 Vaccination: A Systematic Review.
      J Prim Care Community Health. 2022 Feb 1; : 13
      ) In one meta-analysis of 144 patients up to 80% had an accompanying thrombocytopenia and hypofibrinogenemia with a positive PF4 antibodies. (
      • Matar RH
      • Than CA
      • Nakanishi H
      • Daniel RS
      • Smayra K
      • Sim BL
      • et al.
      Outcomes of patients with thromboembolic events following coronavirus disease 2019 AstraZeneca vaccination: a systematic review and meta-analysis.
      Blood Coagul Fibrinolysis. 2022 Mar 1; 33: 90-112
      ) Most patients present to the emergency department and are treated with non-heparin anticoagulants. The mortality rate from CVST is as high as 40%, therefore, timely diagnosis is key. (
      • Jaiswal V
      • Nepal G
      • Dijamco P
      • Ishak A
      • Dagar M
      • Sarfraz Z
      • et al.
      Cerebral Venous Sinus Thrombosis Following COVID-19 Vaccination: A Systematic Review.
      J Prim Care Community Health. 2022 Feb 1; : 13
      )

      Efferent neuro-ophthalmic complications:

      Ocular motility disorders:

      Diplopia is one of the more common symptoms reported post-COVID-19 infection and vaccination. Underlying pathologies vary from cranial nerve palsy and Miller Fisher Syndrome (MFS) to neuromuscular junction disorders like myasthenia gravis (MG), and muscular pathologies like thyroid eye disease (TED) and idiopathic orbital inflammatory syndrome (IOIS).

      Cranial neuropathies

      Post COVID-19 infection:

      In a systematic review, 56 patients with cranial neuropathy associated with COVID-19 were analyzed. Generally, COVID-19 infection was found associated with neuropathies of all cranial nerves (CN) with a predilection for CN VII, VI, and III. (

      Finsterer J, Scorza FA, Scorza CA, Fiorini AC. COVID-19 associated cranial nerve neuropathy: A systematic review. Vol. 22, Bosnian Journal of Basic Medical Sciences. Association of Basic Medical Sciences of FBIH; 2022. p. 39–45.

      ) Isolated cranial neuropathies were more prevalent than multiple cranial neuropathies. Unilateral involvement is more common than bilateral involvement, though bilateral involvement may be a sign of Guillain-Barré syndrome. Treatment included steroids, IVIG, acyclovir/valacyclovir, and rarely PLEX. Complete recovery was seen in 21 patients and partial recovery in 30 patients at discharge or last follow-up.

      Post COVID-19 vaccination:

      After the facial nerve, dysfunction of the abducens nerve is the most common reported neuropathy post-vaccination from any vaccine, followed by the oculomotor and the trochlear nerves. A similar pattern was observed with COVID-19 vaccines. Several reports exist of patients presenting with new onset sixth and third nerve palsy. (
      • Cicalese MP
      • Ferrua F
      • Barzaghi F
      • Cerri F
      • Moro M
      • Aiuti A
      • et al.
      Third cranial nerve palsy in an 88-year-old man after SARS-CoV-2 mRNA vaccination: Change of injection site and type of vaccine resulted in an uneventful second dose with humoral immune response.
      BMJ Case Rep. 2022 Feb 8; 15
      ,

      Kerbage A, Haddad SF, Haddad F. Presumed oculomotor nerve palsy following COVID-19 vaccination. SAGE Open Med Case Rep. 2022 Feb 1;10.

      ,
      • Veisi A
      • Najafi M
      • Hassanpour K
      • Bagheri A
      Facial and Abducens Nerve Palsies Following COVID-19 Vaccination: Report of Two Cases.
      Neuro-Ophthalmology. 2022; 46: 203-206
      ,
      • Pawar N
      • Ravindran M
      • Padmavathy S
      • Chakrabarty S
      Acute abducens nerve palsy after COVID-19 vaccination in a young adult.
      Indian J Ophthalmol. 2021 Dec 1; 69: 3764-3766
      ,
      • Reyes-Capo DP
      • Stevens SM
      • Cavuoto KM
      Acute abducens nerve palsy following COVID-19 vaccination.
      Journal of AAPOS. 2021 Oct 1; 25: 302-303
      ,
      • Basnet K
      • Bhandari R
      • Basnet K
      • Aryal A
      • Shrestha R
      Isolated abducens nerve palsy following AstraZeneca vaccine: A case report.
      Annals of Medicine and Surgery. 2022 Sep 1; : 81
      ,
      • Karam EZ
      • Ríos Macias P
      • Chahin G
      • Kattah JC
      Inflammatory Sixth Nerve Palsy Post-COVID-19 Vaccination: Magnetic Resonance Imaging Findings.
      Neuro-Ophthalmology. 2022; 46: 314-318
      ,
      • Mahgerefteh JS
      • Oppenheimer AG
      • Kay MD
      Binocular Horizontal Diplopia Following mRNA-1273 Vaccine.
      J Neuroophthalmol. 2022 Apr 27;
      ,
      • Pappaterra MC
      • Rivera EJ
      • Oliver AL
      Transient Oculomotor Palsy Following the Administration of the Messenger RNA-1273 Vaccine for SARS-CoV-2 Diplopia Following the COVID-19 Vaccine.
      J Neuroophthalmol. 2023; 43: e14-e15
      ) The onset of diplopia usually was from 1-7 days. It has been reported post BioNTech/Pfizer mRNA-vaccine BNT162b2, Moderna mRNA-1273, Covishield, AstraZeneca ChAdOx1 and Sinopharm. Age ranged from 23-88 years, with no obvious gender predominance. Almost all cases had unilateral involvement (8/9) and normal brain imaging (7/9), with one showing focal enlargement of the root exit zone and the cisternal portion of the left sixth nerve with post-gadolinium enhancement, and the other showing enhancement of both CN6. (
      • Mahgerefteh JS
      • Oppenheimer AG
      • Kay MD
      Binocular Horizontal Diplopia Following mRNA-1273 Vaccine.
      J Neuroophthalmol. 2022 Apr 27;
      ) Two thirds had full spontaneous recovery of symptoms after 2 months, including those with brain imaging abnormalities. Steroids were used in 2/9 patients; one had no response and the other showed complete recovery after 5 days on low-dose steroids.
      Multiple cranial neuropathies also have been reported post-COVID vaccination. One case reported by Manea et al. was of a 29-year-old man with left III, V, VI and VII cranial nerve palsies 6 days after having his first dose of the Pfizer vaccine. (

      Manea MM, Dragoș D, Enache I, Sirbu AG, Tuta S. Multiple cranial nerve palsies following COVID-19 vaccination—Case report. Vol. 145, Acta Neurologica Scandinavica. John Wiley and Sons Inc; 2022. p. 257–259.

      ) Another case by Shalabi et al. was a 41-year-old man with right IV, VI, VII, VIII and X, associated with cervical lymphadenopathy 7 days after receiving his mRNA vaccine. (
      • Shalabi F
      • Lossos A
      • Karussis D
      A case report of unilateral cervical lymphadenopathy and multiple cranial neuropathies following mRNA-COVID-19 vaccination.
      BMC Neurol. 2022 Dec 1; : 22
      ) In both cases, an extensive workup was done, including brain imaging with contrast, infectious and inflammatory lab workup, a lumbar puncture to check for infections and malignant cells and even a full body computed tomography to rule out systemic malignancy were performed. In both cases, an enhancement occurred in post-gadolinium brain imaging of some of the involved cranial nerves, and a short-course of intravenous steroids was administered with subsequent clinical improvement. (

      Manea MM, Dragoș D, Enache I, Sirbu AG, Tuta S. Multiple cranial nerve palsies following COVID-19 vaccination—Case report. Vol. 145, Acta Neurologica Scandinavica. John Wiley and Sons Inc; 2022. p. 257–259.

      ,
      • Shalabi F
      • Lossos A
      • Karussis D
      A case report of unilateral cervical lymphadenopathy and multiple cranial neuropathies following mRNA-COVID-19 vaccination.
      BMC Neurol. 2022 Dec 1; : 22
      ). As with NA-AION, improvement after steroids doesn’t necessarily confirm a treatment affect as the natural history of isolated nerve palsies is for them to improve spontaneously.

      Miller Fisher syndrome

      Post COVID-19 infection:

      MFS is variant of Guillain-Barré syndrome, which is characterized by a triad of ophthalmoplegia, loss of tendon reflexes, and acute onset of ataxia. MFS has been reported after COVID-19 infection and vaccination. Although the number of MFS cases in the context of COVID-19 infection is still increasing, no long-term sequelae were documented. (

      Dinkin M, Sathi S. Efferent neuro-ophthalmic complications of coronavirus disease 2019. Vol. 33, Current Opinion in Ophthalmology. Lippincott Williams and Wilkins; 2022. p. 471–484.

      ,

      Li Z, Li X, Shen J, Chan MT v, Ka W, Wu K. Miller Fisher syndrome associated with COVID-19: an up-to-date systematic review. Environ Sci Pollut Res Int [Internet]. 2021 Mar 6;28(17):20939–44. Available from: https://doi.org/10.1007/s11356-021-13233-w

      ,
      • Kuang W
      • Desai P
      • Voloshko A
      • Jayasekara D
      COVID-19-Associated Miller Fisher Syndrome With Long Latency Period: A Case Report.
      Cureus. 2022 May 1;
      ) A proposed mechanism by which MFS develops is through an immune-mediated post infectious process.(
      • Guilmot A
      • Maldonado Slootjes S
      • Bissay V
      • Dubuisson N
      • de Broglie C
      • Gille M
      SARS-CoV-2-associated Guillain–Barré syndrome in four patients: what do we know about pathophysiology?.
      Acta Neurol Belg. 2022 Jun 1; 122: 703-707
      ) This is supported by the incubation period, the positive response to IVIG, and the presence of anti-ganglioside antibodies in 20% of reported cases.(

      Dinkin M, Sathi S. Efferent neuro-ophthalmic complications of coronavirus disease 2019. Vol. 33, Current Opinion in Ophthalmology. Lippincott Williams and Wilkins; 2022. p. 471–484.

      ,
      • Guilmot A
      • Maldonado Slootjes S
      • Bissay V
      • Dubuisson N
      • de Broglie C
      • Gille M
      SARS-CoV-2-associated Guillain–Barré syndrome in four patients: what do we know about pathophysiology?.
      Acta Neurol Belg. 2022 Jun 1; 122: 703-707
      )

      Post COVID-19 vaccination:

      The onset of symptoms in MFS post-vaccination ranged from 7-18 days. It has been reported after Moderna vaccine, Oxford/AstraZeneca ChAdOx1, BioNTech/Pfizer mRNA-vaccine BNT162b2, tozinameran BNT162b2 mRNA, and CoronaVac-Sinovac Life. Different patterns of ophthalmoplegia were seen in these case reports. (
      • Nanatsue K
      • Takahashi M
      • Itaya S
      • Abe K
      • Inaba A
      A case of Miller Fisher syndrome with delayed onset peripheral facial nerve palsy after COVID-19 vaccination: a case report.
      BMC Neurol. 2022 Dec 1; 22
      ,
      • Dang YL
      • Bryson A
      Miller-Fisher Syndrome and Guillain-Barre Syndrome overlap syndrome in a patient post Oxford-AstraZeneca SARS-CoV-2 vaccination.
      BMJ Case Rep. 2021 Nov 30; 14
      ,
      • Nishiguchi Y
      • Matsuyama H
      • Maeda K
      • Shindo A
      • Tomimoto H
      Miller Fisher syndrome following BNT162b2 mRNA coronavirus 2019 vaccination.
      BMC Neurol. 2021 Dec 1; : 21
      ,
      • Yamakawa M
      • Nakahara K
      • Nakanishi T
      • Nomura T
      • Ueda M
      Miller Fisher Syndrome Following Vaccination against SARS-CoV-2.
      Internal Medicine. 2022; 61: 1067-1069
      ,
      • Siddiqi AR
      • Khan T
      • Tahir MJ
      • Asghar MS
      • Islam MS
      • Yousaf Z
      • et al.
      Miller Fisher syndrome after COVID-19 vaccination: Case report and review of literature.
      Medicine (United States). 2022 May 20; : 101
      ,
      • Michaelson NM
      • Lam T
      • Malhotra A
      • Schiff ND
      • MacGowan DJL
      Miller Fisher Syndrome Presenting After a Second Dose of Pfizer-BioNTech Vaccination in a Patient With Resolved COVID-19_ A Case Report.
      J Clin Neuromuscul Dis. 2021 Dec 1; 23: 113-115
      ,
      • Kim JE
      • Yoon BA
      • Kim YH
      • Kim JK
      • Bae JS
      Miller Fisher syndrome following COVID-19 vaccines: A scoping review.
      Acta Neurol Scand. 2022 Nov 1; 146: 604-609
      ,
      • Abičić A
      • Adamec I
      • Habek M
      Miller Fisher syndrome following Pfizer COVID-19 vaccine.
      Neurological Sciences. 2022 Mar 1; 43: 1495-1497
      ) In 5/7 cases, evidence existed of albuminocytological dissociation in the cerebrospinal fluid sample analysis, which is defined as elevated proteins without pleocytosis. In 3/7 anti-ganglioside antibodies such as anti-GQ1b antibody were positive.(
      • Yamakawa M
      • Nakahara K
      • Nakanishi T
      • Nomura T
      • Ueda M
      Miller Fisher Syndrome Following Vaccination against SARS-CoV-2.
      Internal Medicine. 2022; 61: 1067-1069
      ,
      • Abičić A
      • Adamec I
      • Habek M
      Miller Fisher syndrome following Pfizer COVID-19 vaccine.
      Neurological Sciences. 2022 Mar 1; 43: 1495-1497
      ) Patients were treated with IVIG with recovery taking from weeks to months. One patient received physiotherapy only with reported full spontaneous recovery at 10-weeks follow-up. (
      • Siddiqi AR
      • Khan T
      • Tahir MJ
      • Asghar MS
      • Islam MS
      • Yousaf Z
      • et al.
      Miller Fisher syndrome after COVID-19 vaccination: Case report and review of literature.
      Medicine (United States). 2022 May 20; : 101
      )

      Myasthenia gravis

      Post COVID-19 infection:

      Neuromuscular complications of COVID-19 pose a unique challenge for physicians worldwide. New onset ocular MG has been reported in patients with proven COVID-19 infection.(

      Brossard-Barbosa N, Donaldson L, Margolin E, Editors S, Avery R, Karl Golnik DC, et al. Seropositive Ocular Myasthenia Gravis Developing Shortly After COVID-19 Infection: Report and Review of the Literature Clinical Correspondence. J Neuroophthalmol [Internet]. 2022 Mar 24; Available from: http://links.lww.

      ,
      • Essajee F
      • Lishman J
      • Solomons R
      • Abraham DR
      • Goussard P
      • van Toorn R
      Transient acetylcholine receptor-related myasthenia gravis, post multisystem inflammatory syndrome in children (MIS-C) temporally associated with COVID-19 infection.
      BMJ Case Rep. 2021 Aug 11; : 14
      ,
      • Yavuz P
      • Demir OO
      • Ozsurekci Y
      • Ozen S
      • Anlar B
      • Haliloglu G
      New-Onset Ocular Myasthenia after Multisystem Inflammatory Syndrome in Children.
      Journal of Pediatrics. 2022 Jun 1; 245: 213-216
      ,
      • Huber M
      • Rogozinski S
      • Puppe W
      • Framme C
      • Höglinger G
      • Hufendiek K
      • et al.
      Postinfectious Onset of Myasthenia Gravis in a COVID-19 Patient.
      Front Neurol. 2020 Oct 6; : 11
      ,

      Sriwastava S, Tandon M, Kataria S, Daimee M, Sultan S. New onset of ocular myasthenia gravis in a patient with COVID-19: a novel case report and literature review. Vol. 268, Journal of Neurology. Springer Science and Business Media Deutschland GmbH; 2021. p. 2690–2696.

      ) The incidence of MG was found to be marginally higher in patients with COVID-19 infection compared to general population (0.087% and 0.07% respectively). (
      • Patlolla R
      • Thepmankorn P
      • Heshmati K
      • Malerba S
      • Ruane C
      • Arismendi G
      • et al.
      Myasthenia Gravis After SARS-CoV-2 Infection: A Cerner Real-World COVID-19 De-identified Dataset Analysis.
      Neurology. 2021 Apr; 96
      ) Age has ranged from (6 to 65 years old). Patients complained mostly of diplopia and fatigable ptosis with limitations of ocular motility noted on exam. Treatment comprised of standard dose of pyridostigmine, prednisone, and in some case IVIG. Some of the reported cases had a favorable outcome with complete recovery of their ocular MG, while others had only partial recovery. (

      Brossard-Barbosa N, Donaldson L, Margolin E, Editors S, Avery R, Karl Golnik DC, et al. Seropositive Ocular Myasthenia Gravis Developing Shortly After COVID-19 Infection: Report and Review of the Literature Clinical Correspondence. J Neuroophthalmol [Internet]. 2022 Mar 24; Available from: http://links.lww.

      ,

      Sriwastava S, Tandon M, Kataria S, Daimee M, Sultan S. New onset of ocular myasthenia gravis in a patient with COVID-19: a novel case report and literature review. Vol. 268, Journal of Neurology. Springer Science and Business Media Deutschland GmbH; 2021. p. 2690–2696.

      ) All patients had elevated titers of anti-acetylcholine receptor antibodies. Two cases occurred following a complicated admission with multisystem inflammatory syndrome in children, which recently has been recognized by Centers for Disease Control and Prevention (CDC) as a COVID-19 sequela.(
      • Essajee F
      • Lishman J
      • Solomons R
      • Abraham DR
      • Goussard P
      • van Toorn R
      Transient acetylcholine receptor-related myasthenia gravis, post multisystem inflammatory syndrome in children (MIS-C) temporally associated with COVID-19 infection.
      BMJ Case Rep. 2021 Aug 11; : 14
      ,
      • Yavuz P
      • Demir OO
      • Ozsurekci Y
      • Ozen S
      • Anlar B
      • Haliloglu G
      New-Onset Ocular Myasthenia after Multisystem Inflammatory Syndrome in Children.
      Journal of Pediatrics. 2022 Jun 1; 245: 213-216
      )

      Post COVID-19 vaccination:

      New onset or exacerbation of ocular or generalized MG has been reported after BioNTech/Pfizer mRNA-vaccine BNT162b2, Moderna mRNA-1273, and AstraZeneca ChAdOx1 vaccines. (

      Fanella G, Baiata C, Candeloro E, Toscano G, Colnaghi S, Mauri M, et al. New-onset myasthenia gravis after mRNA SARS-CoV-2 vaccination: a case series. Neurological Sciences. 2022;

      ,

      Ishizuchi K, Takizawa T, Sekiguchi K, Motegi H, Oyama M, Nakahara J, et al. Flare of myasthenia gravis induced by COVID-19 vaccines. Vol. 436, Journal of the Neurological Sciences. Elsevier B.V.; 2022.

      ) The age and gender of those patients mostly followed the demographic of the second peak of MG disease, which is commonly seen in men who are above 60 years of age(
      • Ramdas S
      • Hum RM
      • Price A
      • Paul A
      • Bland J
      • Burke G
      • et al.
      SARS-CoV-2 vaccination and new-onset myasthenia gravis: A report of 7 cases and review of the literature.
      Neuromuscular Disorders. 2022 Oct 1;
      ,
      • Abicic A
      • Sitas B
      • Adamec I
      • Bilic E
      • Habek M
      New-Onset Ocular Myasthenia Gravis After Booster Dose of COVID-19 Vaccine.
      Cureus. 2022 Jul 25;
      ,

      Slavin E, Fitzig J, Neubert C, Garcia-Lopez F, Cuevas-Trisan R. New-Onset Myasthenia Gravis Confirmed by Electrodiagnostic Studies After a Third Dose of SARS-CoV-2 mRNA-1273 Vaccine. Am J Phys Med Rehabil [Internet]. 2022 Dec;101(12):e176–9. Available from: https://journals.lww.com/10.1097/PHM.0000000000002076

      ,
      • Kang MC
      • Park KA
      • Min JH
      • Oh SY
      Myasthenia gravis with ocular symptoms following a ChAdOx1 nCoV-19 vaccination: A case report.
      Am J Ophthalmol Case Rep. 2022 Sep 1; : 27
      ,
      • Hoshina Y
      • Sowers C
      • Baker V
      Myasthenia Gravis Presenting after Administration of the mRNA-1273 Vaccine.
      Eur J Case Rep Intern Med. 2022; 9
      ,
      • Huang BD
      • Hsueh HW
      • Yang SH
      • Lin CW
      New-Onset Myasthenia Gravis After ChAdOx1 nCOV-19 Vaccine Inoculation.
      J Neuroophthalmol. 2022 Mar 24;
      ,
      • Lee MA
      • Lee C
      • Park JH
      • Lee JH
      Early-Onset Myasthenia Gravis Following COVID-19 Vaccination.
      J Korean Med Sci. 2022; 37
      ,

      Maher DI, Hogarty D, ben Artsi E. Acute onset ocular myasthenia gravis after vaccination with the Oxford-AstraZeneca COVID-19 vaccine. Orbit (London). 2022;

      ). Exacerbation of pre-existing MG post-vaccine is thought to be from 1-15%. (
      • Ramdas S
      • Hum RM
      • Price A
      • Paul A
      • Bland J
      • Burke G
      • et al.
      SARS-CoV-2 vaccination and new-onset myasthenia gravis: A report of 7 cases and review of the literature.
      Neuromuscular Disorders. 2022 Oct 1;
      ) Ocular MG cases presented with intermittent fatigable ptosis and diplopia. (
      • Abicic A
      • Sitas B
      • Adamec I
      • Bilic E
      • Habek M
      New-Onset Ocular Myasthenia Gravis After Booster Dose of COVID-19 Vaccine.
      Cureus. 2022 Jul 25;
      ,
      • Kang MC
      • Park KA
      • Min JH
      • Oh SY
      Myasthenia gravis with ocular symptoms following a ChAdOx1 nCoV-19 vaccination: A case report.
      Am J Ophthalmol Case Rep. 2022 Sep 1; : 27
      ,
      • Huang BD
      • Hsueh HW
      • Yang SH
      • Lin CW
      New-Onset Myasthenia Gravis After ChAdOx1 nCOV-19 Vaccine Inoculation.
      J Neuroophthalmol. 2022 Mar 24;
      ,

      Maher DI, Hogarty D, ben Artsi E. Acute onset ocular myasthenia gravis after vaccination with the Oxford-AstraZeneca COVID-19 vaccine. Orbit (London). 2022;

      ) In some of the cases, associated symptoms occurred such as fatigue and weakness, myalgia, dysarthria, dysphagia, and head drop. (
      • Ramdas S
      • Hum RM
      • Price A
      • Paul A
      • Bland J
      • Burke G
      • et al.
      SARS-CoV-2 vaccination and new-onset myasthenia gravis: A report of 7 cases and review of the literature.
      Neuromuscular Disorders. 2022 Oct 1;
      ,

      Slavin E, Fitzig J, Neubert C, Garcia-Lopez F, Cuevas-Trisan R. New-Onset Myasthenia Gravis Confirmed by Electrodiagnostic Studies After a Third Dose of SARS-CoV-2 mRNA-1273 Vaccine. Am J Phys Med Rehabil [Internet]. 2022 Dec;101(12):e176–9. Available from: https://journals.lww.com/10.1097/PHM.0000000000002076

      ,
      • Hoshina Y
      • Sowers C
      • Baker V
      Myasthenia Gravis Presenting after Administration of the mRNA-1273 Vaccine.
      Eur J Case Rep Intern Med. 2022; 9
      ,
      • Lee MA
      • Lee C
      • Park JH
      • Lee JH
      Early-Onset Myasthenia Gravis Following COVID-19 Vaccination.
      J Korean Med Sci. 2022; 37
      ) In 8 of the 11 patients acetylcholine receptors (AchR) antibodies was positive, but none were positive for anti-muscle-specific kinase (MuSK) antibodies. (

      Fanella G, Baiata C, Candeloro E, Toscano G, Colnaghi S, Mauri M, et al. New-onset myasthenia gravis after mRNA SARS-CoV-2 vaccination: a case series. Neurological Sciences. 2022;

      ,
      • Ramdas S
      • Hum RM
      • Price A
      • Paul A
      • Bland J
      • Burke G
      • et al.
      SARS-CoV-2 vaccination and new-onset myasthenia gravis: A report of 7 cases and review of the literature.
      Neuromuscular Disorders. 2022 Oct 1;
      ,
      • Abicic A
      • Sitas B
      • Adamec I
      • Bilic E
      • Habek M
      New-Onset Ocular Myasthenia Gravis After Booster Dose of COVID-19 Vaccine.
      Cureus. 2022 Jul 25;
      ,
      • Kang MC
      • Park KA
      • Min JH
      • Oh SY
      Myasthenia gravis with ocular symptoms following a ChAdOx1 nCoV-19 vaccination: A case report.
      Am J Ophthalmol Case Rep. 2022 Sep 1; : 27
      ,
      • Hoshina Y
      • Sowers C
      • Baker V
      Myasthenia Gravis Presenting after Administration of the mRNA-1273 Vaccine.
      Eur J Case Rep Intern Med. 2022; 9
      ) Electromyography was positive in 5 cases, showing either single-fiber electromyography (SFEMG) test of the orbicularis oculi identified with abnormal jitter or repetitive nerve stimulation providing diagnostic confirmatory for a postsynaptic neuromuscular junction disorder. (

      Fanella G, Baiata C, Candeloro E, Toscano G, Colnaghi S, Mauri M, et al. New-onset myasthenia gravis after mRNA SARS-CoV-2 vaccination: a case series. Neurological Sciences. 2022;

      ,
      • Lee MA
      • Lee C
      • Park JH
      • Lee JH
      Early-Onset Myasthenia Gravis Following COVID-19 Vaccination.
      J Korean Med Sci. 2022; 37
      ,

      Maher DI, Hogarty D, ben Artsi E. Acute onset ocular myasthenia gravis after vaccination with the Oxford-AstraZeneca COVID-19 vaccine. Orbit (London). 2022;

      ) Computed tomography of the chest was negative except for one patient with mild thymic hyperplasia; interestingly, this case was double seronegative. (
      • Lee MA
      • Lee C
      • Park JH
      • Lee JH
      Early-Onset Myasthenia Gravis Following COVID-19 Vaccination.
      J Korean Med Sci. 2022; 37
      ) The treatment of choice was pyridostigmine alone (

      Fanella G, Baiata C, Candeloro E, Toscano G, Colnaghi S, Mauri M, et al. New-onset myasthenia gravis after mRNA SARS-CoV-2 vaccination: a case series. Neurological Sciences. 2022;

      ,
      • Ramdas S
      • Hum RM
      • Price A
      • Paul A
      • Bland J
      • Burke G
      • et al.
      SARS-CoV-2 vaccination and new-onset myasthenia gravis: A report of 7 cases and review of the literature.
      Neuromuscular Disorders. 2022 Oct 1;
      ,
      • Lee MA
      • Lee C
      • Park JH
      • Lee JH
      Early-Onset Myasthenia Gravis Following COVID-19 Vaccination.
      J Korean Med Sci. 2022; 37
      ,

      Maher DI, Hogarty D, ben Artsi E. Acute onset ocular myasthenia gravis after vaccination with the Oxford-AstraZeneca COVID-19 vaccine. Orbit (London). 2022;

      ) or combined with steroids (

      Fanella G, Baiata C, Candeloro E, Toscano G, Colnaghi S, Mauri M, et al. New-onset myasthenia gravis after mRNA SARS-CoV-2 vaccination: a case series. Neurological Sciences. 2022;

      ,
      • Ramdas S
      • Hum RM
      • Price A
      • Paul A
      • Bland J
      • Burke G
      • et al.
      SARS-CoV-2 vaccination and new-onset myasthenia gravis: A report of 7 cases and review of the literature.
      Neuromuscular Disorders. 2022 Oct 1;
      ,
      • Abicic A
      • Sitas B
      • Adamec I
      • Bilic E
      • Habek M
      New-Onset Ocular Myasthenia Gravis After Booster Dose of COVID-19 Vaccine.
      Cureus. 2022 Jul 25;
      ,

      Slavin E, Fitzig J, Neubert C, Garcia-Lopez F, Cuevas-Trisan R. New-Onset Myasthenia Gravis Confirmed by Electrodiagnostic Studies After a Third Dose of SARS-CoV-2 mRNA-1273 Vaccine. Am J Phys Med Rehabil [Internet]. 2022 Dec;101(12):e176–9. Available from: https://journals.lww.com/10.1097/PHM.0000000000002076

      ,
      • Hoshina Y
      • Sowers C
      • Baker V
      Myasthenia Gravis Presenting after Administration of the mRNA-1273 Vaccine.
      Eur J Case Rep Intern Med. 2022; 9
      ,
      • Huang BD
      • Hsueh HW
      • Yang SH
      • Lin CW
      New-Onset Myasthenia Gravis After ChAdOx1 nCOV-19 Vaccine Inoculation.
      J Neuroophthalmol. 2022 Mar 24;
      ) with complete or partial improvement of bulbomotor symptoms in most cases. PLEX was used for 5 days in a patient who showed no signs of improvement. The patient improved clinically after the second round of PLEX and was placed on azathioprine for maintenance(

      Fanella G, Baiata C, Candeloro E, Toscano G, Colnaghi S, Mauri M, et al. New-onset myasthenia gravis after mRNA SARS-CoV-2 vaccination: a case series. Neurological Sciences. 2022;

      ).

      Thyroid eye disease

      TED is an autoimmune disease manifesting with enlargement of the extraocular muscles, proptosis, and eyelid retraction. It commonly is associated with Graves disease (GD). No case reports exist of TED related to COVID-19 infection.

      Post COVID-19 vaccination:

      In a study by Jafarzadeh et al, subacute thyroiditis was found to be the most prevalent thyroid dysfunction after COVID-19 vaccination, followed by GD. TED was reported to be in 1.2% only. (

      Jafarzadeh A, Nemati M, Jafarzadeh S, Nozari P, Mortazavi SMJ. Thyroid dysfunction following vaccination with COVID-19 vaccines: a basic review of the preliminary evidence. Vol. 45, Journal of Endocrinological Investigation. Springer Science and Business Media Deutschland GmbH; 2022. p. 1835–1863.

      ) TED post-COVID-19 vaccination was documented after BioNTech/Pfizer mRNA-vaccine BNT162b2 and Moderna mRNA-1273 vaccine, two were new onset, and two were reactivation. (
      • Rubinstein TJ
      Thyroid Eye Disease Following COVID-19 Vaccine in a Patient With a History Graves’ Disease: A Case Report.
      Ophthalmic Plast Reconstr Surg. 2021 Nov 1; 37: e221-e223
      ,
      • Park K
      • Fung S
      • Ting M
      • Ozzello D
      • Yoon J
      • Liu C
      • et al.
      Thyroid eye disease reactivation associated with COVID-19 vaccination.
      Taiwan J Ophthalmol. 2022 Jan 1; 12: 93-96
      ) Patients were middle-aged women with no history of smoking. Two were previously treated GD patients, one was a treated Hashimoto’s thyroiditis patient, and one had no history of underlying thyroid dysfunction. (
      • Rubinstein TJ
      Thyroid Eye Disease Following COVID-19 Vaccine in a Patient With a History Graves’ Disease: A Case Report.
      Ophthalmic Plast Reconstr Surg. 2021 Nov 1; 37: e221-e223
      ,
      • Park K
      • Fung S
      • Ting M
      • Ozzello D
      • Yoon J
      • Liu C
      • et al.
      Thyroid eye disease reactivation associated with COVID-19 vaccination.
      Taiwan J Ophthalmol. 2022 Jan 1; 12: 93-96
      ) Patients presented with different ocular manifestations of the TED as soon as 1 day and as far as 3 weeks from vaccine administration. Their ocular manifestations ranged from periorbital swelling, chemosis, proptosis, lid retraction, extraocular muscle restriction, and diplopia. Luckily none had any afferent issues on the exam like compressive optic neuropathy. All showed evidence of thyroid dysfunction on laboratory workup except in one case. (
      • Rubinstein TJ
      Thyroid Eye Disease Following COVID-19 Vaccine in a Patient With a History Graves’ Disease: A Case Report.
      Ophthalmic Plast Reconstr Surg. 2021 Nov 1; 37: e221-e223
      ,
      • Park K
      • Fung S
      • Ting M
      • Ozzello D
      • Yoon J
      • Liu C
      • et al.
      Thyroid eye disease reactivation associated with COVID-19 vaccination.
      Taiwan J Ophthalmol. 2022 Jan 1; 12: 93-96
      ) A CT or MRI scan of the brain and orbit demonstrated enlargement of the EOM’s in all of the individuals. Patients responded well to the treatment with Tepezza (Teprotumumab). Spontaneous improvement of symptoms after 4 months was noted in one patient. (
      • Park K
      • Fung S
      • Ting M
      • Ozzello D
      • Yoon J
      • Liu C
      • et al.
      Thyroid eye disease reactivation associated with COVID-19 vaccination.
      Taiwan J Ophthalmol. 2022 Jan 1; 12: 93-96
      )
      IOIS can mimic the presentation of TED, and one case was reported after COVID-19 vaccination. Presenting with diplopia, periorbital erythema, pain and proptosis. Proper investigations and management are prompted in these cases to exclude other causes of orbital inflammation. (

      Yucel Gencoglu A, Mangan MS. Orbital Inflammatory Pseudotumor following mRNA COVID-19 Vaccination. Ocul Immunol Inflamm. 2022;

      ) It is unclear if the association of TED and IOIS with COVID-19 vaccination is due to random chance alone, although it is interesting that most of the cases of TED were in patients who had an underlying predisposition for the disease including two reactivations of TED.

      Pupillary defects:

      Adie’s Tonic pupil

      Post COVID-19 infection:

      Adie’s pupil also has been identified as a potential long-term sequelae of COVID-19 infection. Only two cases are identified in the literature with long-term pupillary abnormalities following COVID-19 infection.(

      Ordás CM, Villacieros-Álvarez J, Pastor-Vivas AI, Corrales-Benítez Á. Concurrent tonic pupil and trochlear nerve palsy in COVID-19. J Neurovirol [Internet]. 2022 Dec 26;6:970–2. Available from: https://doi.org/10.1212/WNL.0000000000009619

      ,
      • Gopal M
      • Ambika S
      • Padmalakshmi K
      Tonic Pupil Following COVID-19.
      J Neuroophthalmol. 2021 Dec 1; 41: e764-e766
      ) Both cases experienced visual dysfunction with evidence of anisocoria three weeks following COVID-19 infection, proven by a positive RT-PCR test or high titer of SARS-CoV-2 IgG antibodies. One patient had findings consistent with right trochlear nerve palsy including right hypertropia on an alternate cover test and right excyclotorsion.(

      Ordás CM, Villacieros-Álvarez J, Pastor-Vivas AI, Corrales-Benítez Á. Concurrent tonic pupil and trochlear nerve palsy in COVID-19. J Neurovirol [Internet]. 2022 Dec 26;6:970–2. Available from: https://doi.org/10.1212/WNL.0000000000009619

      ) Brain imaging using CT and MRI with contrast was unremarkable in both patients. The diagnosis of tonic pupil was confirmed in both cases using a diluted 0.125% pilocarpine test. Treatment consisted of oral corticosteroids, remdesivir, IV antibiotics, dexamethasone, and deriphylline. However, the tonic pupil remained with difficulty focusing near objects despite medical therapy.(
      • Gopal M
      • Ambika S
      • Padmalakshmi K
      Tonic Pupil Following COVID-19.
      J Neuroophthalmol. 2021 Dec 1; 41: e764-e766
      )

      Post COVID-19 vaccination:

      Only one case series exists of Adie’s tonic pupil associated post-COVID-19 vaccination. Gönültas et al described two cases, one was a 27-year-old woman, and another was a 48 years old man, 10 and 12 days after receiving the Pfizer vaccine. , (

      Gönültas¸, EN, Gönültas¸, G, Can GD. Adie Pupil After BNT162b2 mRNA COVID-19 Vaccine. J Neuroophthalmol. 2022 Jul 8;

      ) Both responded to the pharmacological testing using dilute pilocarpine 0.1% with positive constriction of the affected pupil. One had absent deep tendon reflexes and, subsequently, was diagnosed with Holmes-Adie-syndrome. (

      Gönültas¸, EN, Gönültas¸, G, Can GD. Adie Pupil After BNT162b2 mRNA COVID-19 Vaccine. J Neuroophthalmol. 2022 Jul 8;

      )

      Horner syndrome:

      One report exists of a transient isolated Horner syndrome (HS) in a 65-years-old woman 3 days after being infected with COVID-19.(

      Naor MS, Mathew PG, Sharon R. Transient Horner syndrome associated with COVID-19: A case report. Vol. 25, eNeurologicalSci. Elsevier B.V.; 2021.

      ) The patient had a normal workup including CT/CTA head, neck, and brain MRI with and without gadolinium. Complete resolution of her ptosis and miosis after 8 days of symptoms onset.(

      Naor MS, Mathew PG, Sharon R. Transient Horner syndrome associated with COVID-19: A case report. Vol. 25, eNeurologicalSci. Elsevier B.V.; 2021.

      ) HS has not been reported yet in association with COVID-19 vaccination.

      Proposed mechanisms of neuro-ophthalmic complications post COVID-19 infection:

      While the pathophysiology in the course of COVID-19 infection is not fully understood, several mechanisms have been proposed to explain neuro-ophthalmic manifestations from COVID-19 infection, most favoring an immune-mediated background. The SARS-CoV-2 virus may be implicated through molecular mimicry, inducing an autoimmune response, and causing disorders such as ON and MG.(
      • Rojas-Correa DX
      • Reche-Sainz JA
      • Insausti-García A
      • Calleja-García C
      • Ferro-Osuna M
      Post COVID-19 Myelin Oligodendrocyte Glycoprotein Antibody-Associated Optic Neuritis.
      Neuro-Ophthalmology. 2021;
      ,
      • Rodríguez-Rodríguez MS
      • Romero-Castro RM
      • Alvarado-de la Barrera C
      • González-Cannata MG
      • García-Morales AK
      • Ávila-Ríos S
      Optic neuritis following SARS-CoV-2 infection.
      J Neurovirol. 2021 Apr 1; 27: 359-363
      ,
      • Huber M
      • Rogozinski S
      • Puppe W
      • Framme C
      • Höglinger G
      • Hufendiek K
      • et al.
      Postinfectious Onset of Myasthenia Gravis in a COVID-19 Patient.
      Front Neurol. 2020 Oct 6; : 11
      ,

      Peters J, Alhasan S, Vogels CBF, Grubaugh ND, Farhadian S, Longbrake EE. MOG-associated encephalitis following SARS-COV-2 infection. Vol. 50, Multiple Sclerosis and Related Disorders. Elsevier B.V.; 2021.

      ,

      Lucchese G, Flöel A. Molecular mimicry between SARS-CoV-2 and respiratory pacemaker neurons. Vol. 19, Autoimmunity Reviews. Elsevier B.V.; 2020.

      )
      The SARS-CoV-2 virus also has been reported to have a neurotoxic effect through binding to the angiotensin enzyme 2 (ACE2) receptor which is an important entry receptor for the virus to vital organs like the brain. Direct viral infection could explain some of the autoimmune disorders occurring in patients post COVID-19 infection such as optic neuritis, cranial neuropathies, and Adie’s tonic pupils(
      • Mabrouki FZ
      • Sekhsoukh R
      • Aziouaz F
      • Mebrouk Y
      Acute Blindness as a Complication of Severe Acute Respiratory Syndrome Coronavirus-2.
      Cureus. 2021 Aug 3;
      ,

      Finsterer J, Scorza FA, Scorza CA, Fiorini AC. COVID-19 associated cranial nerve neuropathy: A systematic review. Vol. 22, Bosnian Journal of Basic Medical Sciences. Association of Basic Medical Sciences of FBIH; 2022. p. 39–45.

      ,

      Kahloun R, Abroug N, Ksiaa I, Mahmoud A, Zeghidi H, Zaouali S, et al. Infectious optic neuropathies: A clinical update. Vol. 7, Eye and Brain. Dove Medical Press Ltd.; 2015. p. 59–81.

      ,
      • Kaya Tutar N
      • Kale N
      • Tugcu B
      Adie-Holmes syndrome associated with COVID-19 infection: A case report.
      Indian J Ophthalmol. 2021 Mar 1; 69: 773-774
      ) Retrograde transport of the virus particles to the central nervous system is thought to underlie some of these disorders and is supported by a post-mortem case series that found that SARS-CoV-2 viral proteins in the cranial nerves of (53%) of the investigated patients.(
      • Matschke J
      • Lütgehetmann M
      • Hagel C
      • Sperhake JP
      • Schröder AS
      • Edler C
      • et al.
      Neuropathology of patients with COVID-19 in Germany: a post-mortem case series.
      Lancet Neurol. 2020 Nov 1; 19: 919-929
      ) Also, viral particles are thought to travel from the lungs to the autonomic center in the brain stem causing disorders like Horner syndrome (HS).(

      Naor MS, Mathew PG, Sharon R. Transient Horner syndrome associated with COVID-19: A case report. Vol. 25, eNeurologicalSci. Elsevier B.V.; 2021.

      ) Moreover, in cases like GCA, the virus is thought to have an affinity to the vascular endothelium causing direct damage. (
      • Szydełko-Paśko U
      • Przeździecka-Dołyk J
      • Kręcicka J
      • Małecki R
      • Misiuk-Hojło M
      • Turno-Kręcicka A
      Arteritic Anterior Ischemic Optic Neuropathy in the Course of Giant Cell Arteritis After COVID-19.
      American Journal of Case Reports. 2022; 23
      ,
      • Riera-Marti N
      • Romani J
      • Calvet J
      SARS-CoV-2 infection triggering a giant cell arteritis.
      Med Clin (Barc). 2021; 156: 253-254
      ) The SARS-CoV-2 virus can cause a disruption the blood-brain barrier by pro-inflammatory cytokines and result in increased permeability of the blood-brain barrier, which gives access for antibodies such as myelin oligodendrocyte glycoprotein (MOG) antibodies to the central nervous system. (
      • Zhou S
      • Jones-Lopez EC
      • Soneji DJ
      • Azevedo CJ
      • Patel VR
      Myelin Oligodendrocyte Glycoprotein Antibody-Associated Optic Neuritis and Myelitis in COVID-19.
      J Neuroophthalmol. 2020 Jun 26;
      )
      Reports also have suggested that COVID-19-induced hypoxemia and hypercoagulability can increase the risk of circulatory insufficiency and NA-AION.(

      Dhont S, Derom E, van Braeckel E, Depuydt P, Lambrecht BN. The pathophysiology of “happy” hypoxemia in COVID-19. Vol. 21, Respiratory Research. BioMed Central Ltd; 2020.

      ,
      • Tang N
      • Li D
      • Wang X
      • Sun Z
      Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia.
      Journal of Thrombosis and Haemostasis. 2020 Apr 1; 18: 844-847
      ) Also, hypercoagulability and hyperviscosity can lead to venous congestion and Idiopathic intracranial hypertension (IIH) or cerebral venous sinus thrombosis (CVST). (
      • Silva MTT
      • Lima MA
      • Torezani G
      • Soares CN
      • Dantas C
      • Brandão CO
      • et al.
      Isolated intracranial hypertension associated with COVID-19.
      Cephalalgia. 2020 Nov 1; 40: 1452-1458
      ,
      • Matar RH
      • Than CA
      • Nakanishi H
      • Daniel RS
      • Smayra K
      • Sim BL
      • et al.
      Outcomes of patients with thromboembolic events following coronavirus disease 2019 AstraZeneca vaccination: a systematic review and meta-analysis.
      Blood Coagul Fibrinolysis. 2022 Mar 1; 33: 90-112
      )

      Proposed mechanism of neuro-ophthalmic complications post COVID-19 vaccination:

      Multiple mechanisms have been proposed for post-vaccine-related complications, some are very similar to those proposed for post COVID-19 infection. One is the molecular mimicry theory, where the vaccine introduces proteins to the host that mimic self-antigens or similar conformational structures. In the case of optic neuritis, the molecular mimicry between the virus and CNS myelin, where they share the same amino acid sequence, leads to the formation of antibodies that attack myelin and cause demyelination. (

      Badeeb N, Torres C, Albreiki D. Case of Bilateral Optic Neuritis With Positive Myelin Oligodendrocyte Glycoprotein Antibody Testing Post-COVID-19 Vaccination. J Neuroophthalmol [Internet]. 2022 Apr 28; Available from: http://journals.lww.com/jneuro-ophthalmology

      )This theory also has been proposed for cranial neuropathies post-vaccination where autoimmune inflammatory demyelinating peripheral neuropathy occurs. (
      • Cicalese MP
      • Ferrua F
      • Barzaghi F
      • Cerri F
      • Moro M
      • Aiuti A
      • et al.
      Third cranial nerve palsy in an 88-year-old man after SARS-CoV-2 mRNA vaccination: Change of injection site and type of vaccine resulted in an uneventful second dose with humoral immune response.
      BMJ Case Rep. 2022 Feb 8; 15
      ,

      Kerbage A, Haddad SF, Haddad F. Presumed oculomotor nerve palsy following COVID-19 vaccination. SAGE Open Med Case Rep. 2022 Feb 1;10.

      ,
      • Karam EZ
      • Ríos Macias P
      • Chahin G
      • Kattah JC
      Inflammatory Sixth Nerve Palsy Post-COVID-19 Vaccination: Magnetic Resonance Imaging Findings.
      Neuro-Ophthalmology. 2022; 46: 314-318
      ) A similar mechanism is well established in Miller-Fisher Syndrome (MFS) where molecular mimicry may induce GQ1b or GT1a ganglioside antibody production and cause a secondary, acute, demyelinating, inflammatory polyneuropathy affecting the peripheral nervous system.(
      • Dang YL
      • Bryson A
      Miller-Fisher Syndrome and Guillain-Barre Syndrome overlap syndrome in a patient post Oxford-AstraZeneca SARS-CoV-2 vaccination.
      BMJ Case Rep. 2021 Nov 30; 14
      ,
      • Nishiguchi Y
      • Matsuyama H
      • Maeda K
      • Shindo A
      • Tomimoto H
      Miller Fisher syndrome following BNT162b2 mRNA coronavirus 2019 vaccination.
      BMC Neurol. 2021 Dec 1; : 21
      ) Likewise in MG, the host immune system perceives the vaccine antigen as similar to host acetylcholine receptors (AChR) and attacks those receptors.(
      • Ramdas S
      • Hum RM
      • Price A
      • Paul A
      • Bland J
      • Burke G
      • et al.
      SARS-CoV-2 vaccination and new-onset myasthenia gravis: A report of 7 cases and review of the literature.
      Neuromuscular Disorders. 2022 Oct 1;
      ,
      • Abicic A
      • Sitas B
      • Adamec I
      • Bilic E
      • Habek M
      New-Onset Ocular Myasthenia Gravis After Booster Dose of COVID-19 Vaccine.
      Cureus. 2022 Jul 25;
      ,
      • Kang MC
      • Park KA
      • Min JH
      • Oh SY
      Myasthenia gravis with ocular symptoms following a ChAdOx1 nCoV-19 vaccination: A case report.
      Am J Ophthalmol Case Rep. 2022 Sep 1; : 27
      ,
      • Huang BD
      • Hsueh HW
      • Yang SH
      • Lin CW
      New-Onset Myasthenia Gravis After ChAdOx1 nCOV-19 Vaccine Inoculation.
      J Neuroophthalmol. 2022 Mar 24;
      ,

      Maher DI, Hogarty D, ben Artsi E. Acute onset ocular myasthenia gravis after vaccination with the Oxford-AstraZeneca COVID-19 vaccine. Orbit (London). 2022;

      )
      The other theory is the presence of adjuvant material in some of the vaccines, which are added to the vaccine to enhance immune response but may also produce an unwanted exaggerated immune reaction. This material is thought to play a role in the pathogenesis of an autoimmune syndrome associated with adjuvants ASIA that can possibly explain ON, GCA and MG post-vaccination. (
      • García-Estrada C
      • Gómez-Figueroa E
      • Alban L
      • Arias-Cárdenas A
      Optic neuritis after COVID-19 vaccine application.
      Clin Exp Neuroimmunol. 2022 May 1; 13: 72-74
      ,
      • Huang BD
      • Hsueh HW
      • Yang SH
      • Lin CW
      New-Onset Myasthenia Gravis After ChAdOx1 nCOV-19 Vaccine Inoculation.
      J Neuroophthalmol. 2022 Mar 24;
      ,
      • Nichani P
      • Micieli JA
      Granuloma Annulare, Scalp Necrosis, and Ischemic Optic Neuropathy From Giant Cell Arteritis After Varicella-Zoster Virus Vaccination.
      J Neuroophthalmol. 2021 Jun 1; 41: e145-e148
      )
      Similarly, the vaccine could work to trigger and unmask the disease in individuals who were genetically predisposed to develop autoimmune diseases such as in patients with ON, GCA, TED and MG. (

      Badeeb N, Torres C, Albreiki D. Case of Bilateral Optic Neuritis With Positive Myelin Oligodendrocyte Glycoprotein Antibody Testing Post-COVID-19 Vaccination. J Neuroophthalmol [Internet]. 2022 Apr 28; Available from: http://journals.lww.com/jneuro-ophthalmology

      ,
      • Lee MA
      • Lee C
      • Park JH
      • Lee JH
      Early-Onset Myasthenia Gravis Following COVID-19 Vaccination.
      J Korean Med Sci. 2022; 37
      ,
      • Rubinstein TJ
      Thyroid Eye Disease Following COVID-19 Vaccine in a Patient With a History Graves’ Disease: A Case Report.
      Ophthalmic Plast Reconstr Surg. 2021 Nov 1; 37: e221-e223
      ) Especially in those with symptoms occurring within a few days after receiving the vaccine. (
      • Stübgen JP
      A literature review on optic neuritis following vaccination against virus infections.
      Autoimmunity Reviews. 2013; 12: 990-997
      )The presence of the human leukocyte antigen (HLA) DRB1*16:02 genotype in patients with GCA also supports the genetic predisposition theory.
      It is thought that endothelial cell dysfunction secondary to neuroinflammation from the vaccine can lead to hypercoagulopathy, hyperviscosity, thrombosis, and venous stasis. Subsequently, this might lead to cranial neuropathies, (
      • Pappaterra MC
      • Rivera EJ
      • Oliver AL
      Transient Oculomotor Palsy Following the Administration of the Messenger RNA-1273 Vaccine for SARS-CoV-2 Diplopia Following the COVID-19 Vaccine.
      J Neuroophthalmol. 2023; 43: e14-e15
      ) NA-AION and IIH. (
      • Sitaula S
      • Poudel A
      • Gajurel BP
      Non-arteritic anterior ischemic optic neuropathy in COVID-19 infection – A case report.
      Am J Ophthalmol Case Rep. 2022 Sep 1; : 27
      ,
      • Farahani AA
      • Shahali H
      Intracranial Hypertension and Papilledema: An Unusual Complication After the Adenoviral DNA Vector–Based Coronavirus Disease 2019 Vaccination in an Air Medical Transportation Pilot.
      Air Med J. 2022;
      ,
      • Thunstedt DC
      • Straube A
      • Schöberl F
      Isolated intracranial hypertension following COVID-19 vaccination: A case report.
      Cephalalgia Rep. 2021; : 4
      ).

      Conclusion:

      To date COVID-19 infection and vaccines have been associated with neuro-ophthalmic complications but causation remains to be proven. At the moment, most of our information comes from case reports and case series yet the literature is still growing with the continuation of the global pandemic and vaccination programs. It’s important to remember that these neuro-ophthalmic conditions still occurred in the absence of COVID-19 and given the billions of cases of COVID-19 infection and vaccines which have been administered worldwide, overlap is inevitable due to random chance alone. It also is important to note that while COVID-19 vaccines may be associated with neuro-ophthalmic sequela, COVID-19 is a deadly disease with its own long term sequela, and the sequela post-vaccination are treatable with almost universally good outcomes if recognized and treated early. Insufficient evidence exists to justify the deferment of vaccination based on these very rare neuro-ophthalmic associations, some of which are highly likely due to random chance alone. Both the SARS-CoV-2 virus and all the vaccines that have been produced to combat this global pandemic may have the potential to cause or exacerbate neuro-ophthalmic conditions, and ophthalmologists should be mindful of this potential and treat accordingly.

      Clinics Care Points

      • •
        Consider SARS-CoV-2 infection and ask about COVID-19 symptoms when presented with an otherwise unexplained cranial neuropathy.
      • •
        Treat patients in accordance with best practices for the clinical neuro-ophthalmic phenotype with which they present irrespective of any COVID-19 association.
      • •
        Understand that post-COVID conditions can occur months after the COVID-19 infection.

      References

      1. World Health Organization. (2020). Novel Coronavirus (2019-nCoV): situation report, 11. World Health Organization. [Internet]. [cited 2022 May 20]. Available from: https://apps.who.int/iris/handle/10665/330776

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      Article info

      Publication history

      Publication stage

      In Press Accepted Manuscript

      Footnotes

      Conflict of interest: none

      Source of support: none

      Acknowledgment: We would like to acknowledge Ms. Risa Shorr our medical librarian for her collaboration and help in the literature review process.

      Identification

      DOI: https://doi.org/10.1016/j.yaoo.2023.03.004

      Copyright

      Crown Copyright © 2023 Published by Elsevier Inc. All rights reserved.

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