Diplopia, COVID-19 and Vaccination: Results from a Cross-Sectional Study in Croatia

Abstract

The aim of this study was to explore diplopia as a symptom of undetected COVID-19 infection or as a possible side effect of COVID-19 vaccination. We examined 380 patients with diplopia admitted to the Department of Ophthalmology of the University Hospital Centre Sestre milosrdnice in Zagreb, Croatia, from July 2020 to June 2022. After excluding patients with confirmed organic underlying diplopia causes or monocular diplopia, we linked the patient information with the national COVID-19 and vaccination registries. Among the 91 patients included in this study, previously undetected COVID-19 infection as the possible cause of diplopia was confirmed in five of them (5.5%). An additional nine patients (9.9%) were vaccinated within one month from the onset of their symptoms, while the remaining 77 had neither and were therefore considered as controls. The breakdown according to the mechanism of diplopia showed no substantial difference between the vaccinated patients and the controls. We detected marginally insignificant excess abducens nerve affection in the COVID-positive group compared with that in the controls (p = 0.051). Post-vaccination diplopia was equally common in patients who received vector-based or RNA-based vaccines (21.4 vs. 16.7%; p = 0.694). COVID-19 testing should be performed for all cases of otherwise unexplained diplopia. The risk of post-vaccination diplopia was similar in both types of vaccines administered, suggesting a lack of evidence linking specific vaccine types to diplopia.

1. Introduction

Diplopia is an early sign of a muscular or neurologic pathological process affecting the eyes [1]. It reflects dysfunction of the extraocular muscles due to mechanical problems, neuromuscular junction disorders, cranial nerve palsy, supranuclear oculomotor pathway disorders, or toxin ingestion [2]. Diplopia can occur in various conditions, including strabismus, hypertension, diabetes, head and eye trauma, demyelination, malignancy, inflammation, infection, and autoimmune disease [3]. The most common causes of diplopia among autoimmune diseases include Graves’ disease, Hashimoto’s thyroiditis, Guillain–Barre syndrome, myasthenia gravis (MG), dermatomyositis, and systemic sclerosis [4]. Although diplopia occurs most often in Graves’ disease [5], myasthenia gravis was the leading cause of binocular diplopia-related ambulatory setting visits in the United States, according to De Lotts’ cross-sectional, population-based survey data [6]. Diplopia has been implied as a pathological sign associated with various infections [7], including acute viral infections [8,9,10,11,12]. Interestingly, it has also been reported as a possible anti-viral vaccination side effect [13] for polio [14], yellow fever [15], hepatitis B [16], or Japanese encephalitis [17].

The link between COVID-19 and diplopia has been a matter of ongoing debate, with various neuro-ophthalmologic symptoms and complications [18,19,20,21,22,23,24,25,26,27]. Interestingly, diplopia was also reported in asymptomatic SARS-CoV-2 infection, suggesting that it might also be a symptom of a previously undetected infection [28]. Several mechanisms causing diplopia were implied in COVID-19, including oculomotor nerve palsy [29,30,31], trochlear [32], or abducens nerve palsy [33,34,35,36,37,38,39,40,41]. The most likely underlying pathogenetic process involves immune reactions that are mediated by several classes of antibodies, namely anti-GQ1b immunoglobulin G (IgG) [42,43,44], previously being implicated in several neuro-ophthalmic disorders [45]; anti-GT1a IgG [44], involved in neurological disorders such as Guillain–Barre syndrome [46]; MOG antibodies [47], implicated in several myelin-related disorders [48]; or anti-GD1b, involved in neuromuscular junction disorders and MG [49]. Summarised evidence suggests that SARS-CoV-2 infection can trigger numerous autoimmune disorders [49], leading to unfavourable clinical outcomes [50]. In addition to being reported after acute SARS-CoV-2 infection, diplopia has also been reported by several previous studies after COVID-19 vaccination, raising concerns about this being possibly one of the less documented vaccination side effect [51,52,53,54]. The pathogenesis underlying these associations is unclear, but some interesting patterns can be identified. There is a substantial co-occurrence of COVID and MG, and both COVID infection and vaccines were implicated as a possible MG trigger [55]. Numerous underlying mechanisms were implicated, including molecular mimicry, immunosomes, and reactions related to “adjuvants” in vaccines [56,57]. A recent analysis reported an increased rate of vaccination side effects in a cohort of MG patients, with nearly 50% mortality in the unvaccinated subgroup of MG patients [57].

The COVID-19 pandemic has caused numerous disruptions in regular healthcare functioning, especially monitoring and surveillance [58]. Despite a quick response in Croatia and a functional data collection system deployed within weeks of the pandemic’s start [59], substantial changes and challenges in the diagnostics were identified [60] alongside constantly changing epidemic patterns, preventing the proper calculation of epidemiological rates [61,62,63].

Therefore, the aim of this study was to explore if incidental diplopia cases were associated with undetected COVID-19 or as a possible vaccination side effect based on the data from a tertiary-level clinical hospital in Croatia.

2. Materials and Methods

For the purposes of this study, we examined the medical records of all patients hospitalised for diplopia from 1 July 2020 to 1 June 2022 at the Department of Ophthalmology of the University Hospital Centre Sestre milosrdnice in Zagreb, Croatia. We included patients who were initially admitted with diplopia, including all who were assigned the following International Classification of Diseases (ICD-10) codes: H53.2 Diplopia; H49.0 Third (oculomotor) nerve palsy; H49.1 Fourth (trochlear) nerve palsy; H49.2 Sixth (abducent) nerve palsy; H49.3 Total (external) ophthalmoplegia; H49.4 Progressive external ophthalmoplegia; H49.8 Other paralytic strabismus; H49.9 Paralytic strabismus, unspecified; H51.0 Palsy of conjugate gaze; and H51.2 Internuclear ophthalmoplegia. Next, we performed a detailed search of their medical records, removing all cases of monocular diplopia. Additionally, we excluded all patients in which we could confirm restrictive strabismus (distyroid orbitopathy and extraocular muscle trauma), latent (heterophoria) and manifest strabismus of non-paralytic aetiology, tumour process of the central nervous system (CNS), and postoperative deficit involving the CNS, aneurysms and other causes (incomplete medical records, pansinusitis, and general endotracheal anaesthesia). Following this, we linked their data with the national COVID-19 and vaccination registries run by the Croatian Institute of Public Health to verify their infection and vaccination statuses. Based on this data linking, we classified all patients into three groups: likely COVID-19-caused diplopia (CoVd), likely post-vaccine diplopia (pVd), and controls (cc). In order to be classified as the likely COVID-19-caused diplopia, a patient had to be diagnosed with COVID-19 within one month of the diplopia onset (0–30 days). The second group, likely post-vaccine diplopia, was ascertained in those instances when a vaccine (the first or the second dose) was administered within one month from diplopia onset. Therefore, the onset of their diplopia had to occur within 30 days from vaccination. Lastly, patients diagnosed with diplopia who were not diagnosed with COVID-19 or were not vaccinated within the past month were considered a control group, reflecting the baseline risk of diplopia.

In all instances, diplopia was diagnosed by a detailed strabological clinical examination, aiming to identify paretic muscles. The examination included an eye movement examination in each of the nine gaze directions, a red glass test, a Bagolini striated glasses test (BSGT), and the measurement of the angle of ocular deviation (squint angle) at far and near distances using the alternate prism cover test (APCT).

2.1. Ethics

The study was based exclusively on secondary data, and no contact with the patients was made for the purposes of this study. The approval for this study was issued by the Ethical Panel of the University Hospital Centre Sestre milosrdnice, designated as document 251-29-11-21-01-2.

2.2. Statistics

Due to a small number of cases in two of the three groups analysed, the categorical data were analysed with Fisher’s exact test (two-tailed). The numerical data were analysed with a t-test. Two models of logistic regression were made, used to provide adjustment for the most apparent confounders. The model for likely post-vaccination diplopia was based on sex; age; presence of comorbidities (including diagnosed hypertension, hyperlipidaemia, diabetes mellitus, atrial fibrillation, cardiomyopathy, renal insufficiency, rheumatoid arthritis, and previous thrombotic events); and vaccine type, classified as vector-based vs. RNA-based. The vector-based vaccine type administered in Croatia is ChAdOx1, and the two RNA-based vaccines used in Croatia are BNT162b2 and mRNA-1273. The model for likely post-COVID diplopia included only sex, age, and the presence of comorbidities. In both cases, we assessed model fit using the Hosmer–Lemeshow test and correctly classified the number of cases from the classification table. All analyses were performed in R (www.r-project.org, accessed on 15 June 2022), with significance set at p < 0.05.

3. Results

There were 91 patients with binocular diplopia involved in this study, belonging to three study groups: likely post-vaccination diplopia (pVd; n = 9), diplopia in COVID-19 patients (CoVd, n = 5), and diplopia in patients who were neither confirmed cases nor vaccinated and were therefore considered as controls (cc; n = 77). The initial comparison of these groups revealed no significant differences in age, gender, and comorbidities existence, although both groups of cases were, on average, younger (Table 1).

The vaccine type was not associated with diplopia diagnosed within one month after vaccination vs. at any other time (Table 2).

Finally, we calculated the multivariate models, adjusted for the effects of age, sex, and comorbidities; notably, the post-vaccination model also included vaccine type (Table 3). Despite the very small number of cases, both models satisfied the diagnostic criteria (Hosmer–Lemeshow test p = 0.845 with 84.3% correctly classified cases for pVd, and p = 0.513 with 93.9% of correctly classified cases for CoVd). Notably, neither of the predictor variables reached statistical significance (Table 3).

4. Discussion

The results of this study might suggest that diplopia should be considered a possible symptom of a previously undetected COVID-19/SARS-CoV-2 infection. This is in line with the clinical appearance of the virus and previous reports, which showed a substantial tendency to affect cranial nerves and to cause neurological or ophthalmic symptoms [18,19,28,64]. Interestingly, we detected a nearly significant surplus of abducens nerve affections in COVID-19 cases, despite previous suggestions of the abducens nerve being the least commonly affected cranial nerve [26]. The difference probably arises from the sample composition; while the previous study focused on COVID-19-positive patients, this study was based on patients with diplopia. Nevertheless, one of the most salient results of this study is the recommendation to include SARS-CoV-2 testing as a mandatory element of the diagnostic protocol in otherwise unexplained diplopia.

This study did not provide a clear answer to the question of whether diplopia should be considered one of the possible side effects of COVID-19 vaccination. This finding is in line with several recent studies [57,65,66,67]. In addition to the common problems arising from vaccination side-effect surveillance [68,69], we were further limited due to an inability to calculate proper rates during the pandemic [62], as well as the organisational issue related to hospitals merging and gravitational areas changing, therefore disabling a more detailed time-series and rates analysis. However, this study did show that the underlying mechanisms of diplopia were similar in the controls and the post-vaccination group, suggesting that the risk of post-vaccination diplopia resembles the risk at baseline (vaccination-free). Furthermore, we detected no difference in the diplopia occurrence in patients who received vector-based vs. RNA-based vaccines. Previous comparisons often reflected substantial differences in the side-effect profiles between such vaccines [70], suggesting that the observed profile is more likely to reflect the baseline risk of diplopia and is unrelated to vaccination. However, such a finding should be replicated in an independent cohort before we can provide a more reliable answer to diplopia being considered a COVID-19 vaccination side effect. Notably, several other studies that investigated the ophthalmic side effects of the COVID-19 vaccine did not report diplopia as a side effect, further contributing to the low likelihood of diplopia arising from COVID-19 vaccination [71,72,73,74,75].

The limitations of this study are numerous, with most due to previously mentioned difficulties in obtaining comparable data during the epidemic and the peri-epidemic periods, with a spectrum of differences in the type of health care delivered during such times, which prevents direct comparisons and the calculation of epidemiological rates. Therefore, we did not provide the rates of events in this study, having considered them inherently biased. Additionally, any side-effect reporting system is always methodologically challenging [69,76], with possible upwardly biased estimates during the pandemic due to very prevalent awareness and even anti-vaccination campaigns. This limits direct comparisons of the side-effect rates with the pre-pandemic estimates [77]. This study further suffers from overall small sample sizes, meaning that it was prone to type I errors and that all of these conclusions cannot be used for a definitive answer but can only contribute to the overall discussion. In light of this, further data collection and analyses in independent cohorts and populations are required [27,78]. Clinical examination was another possible source of bias, so we could not establish the clinical course timeline or ascertain the viral and immunological dynamics. In addition, the inclusion of the Hess–Lancaster test could have provided an additional assessment element, but it was not performed. One of the limitations is related to the group of patients with unknown diplopia pathogenesis. This group is possibly the most interesting for understanding the disease pathogenesis and, possibly, the early stages of various other diseases, notably myasthenia gravis. A possible solution would include longer follow-up periods for such patients, during which their clinical manifestations would become more apparent. However, the overall evidence was insufficient to suggest the causal relationship between vaccination and diplopia occurrence, while the link between asymptomatic infection and diplopia seems more likely.

Author Contributions

Conceptualisation, J.Š.H., Z.V. and O.P.; methodology, J.Š.H., V.M. and O.P.; formal analysis, O.P. and J.Š.H.; investigation, J.Š.H., G.M., M.M.R., L.K., I.J., E.S., I.P.V. and Z.V.; data curation, O.P.; writing—original draft preparation, J.Š.H. and O.P.; writing—review and editing, all authors. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Ethical Panel of the University Hospital Centre Sestre milosrdnice, designated as document 251-29-11-21-01-2.

Informed Consent Statement

Patient consent was waived due to secondary use of data taken from medical records; no contact with the patients was made for the purposes of this study.

Data Availability Statement

The raw data are available upon reasonable request to the corresponding author.

Conflicts of Interest

OP is a scientific advisor to the Government of the Republic of Croatia for COVID-19 response, which had no influence in the decision to prepare the manuscript, its preparation or the selection of the journal where the manuscript would be submitted. The remaining authors declare that the study was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Tables

Table 1

The comparison of the three study groups.

	Group			Significance (P)
	pVd (Post-Vaccination)	CoVd (Undetected COVID)	cc (Controls)	pV vs. cc	CoV vs. cc
Age (years); mean ± SD	54.33 ± 18.70	52.40 ± 16.40	62.81 ± 18.39	0.195	0.221
Women; n (%)	5 (55.6)	4 (80.0)	40 (51.9)	~1	0.366
Comorbidities present; n (%)	6 (66.7)	3 (60.0)	49 (63.6)	~1	~1
Diplopia mechanisms; n (%)
Cranial nerve (CN) paresis *
CN III, right	1 (11.1)	0	3 (3.9)
CN III, left	1 (11.1)	0	11 (14.3)
CN III, binocular	0	0	2 (2.6)
Subtotal, CN III	2 (22.2)	0	16 (20.8)	~1	0.577
CN IV, right	0	0	1 (1.3)
CN IV, left	0	1 (20.0)	3 (3.9)
CN IV, binocular	0	0	0
Subtotal, CN IV	0	1 (20.0)	4 (5.2)	~1	0.276
CN VI, right	1 (11.1)	3 (60.0)	6 (7.8)
CN VI, left	0	1 (20.0)	14 (18.2)
CN VI, binocular	1 (11.1)	0	5 (6.5)
Subtotal, CN VI	2 (22.2)	4 (80.0)	25 (32.5)	0.713	0.051
Internuclear ophthalmoplegia	1 (11.1)	0	0
Vertical strabismus	0	0	1 (1.3)
Cranial nerve neuritis	0	0	1 (1.3)
Unknown pathogenesis	4 (44.4)	0	30 (39.0)
Subtotal, other	5 (55.5)	0	32 (41.6)	0.473	0.151
Total	9	5	77

* Due to a very low number of cases, only the sub-total number per nerve was tested statistically.

Table 2

Post-vaccine diplopia risk in vector- and RNA-based vaccinated patients.

Vaccination Type	Diplopia Occurrence		P
	Within One Month after Vaccination (n = 9)	At Some Other Time (n = 41)
Vector-based vaccine	3 (21.4)	11 (78.6)	0.694
RNA-based vaccine *	6 (16.7)	30 (83.3)

* Including different combinations of RNA-based vaccines.

Table 3

A logistic regression model used to explore the differences between likely post-vaccination diplopia (pVd) and likely COVID-caused diplopia (CoVd).

	Likely Post-Vaccine Diplopia (pVd)		Likely Post-COVID Diplopia (CoVd)
Predictor Variable	OR [95% CI]	p	OR [95% CI]	p
Age	0.94 [0.88–1.01]	0.056	0.96 [0.90–1.02]	0.155
Sex
Men (Ref.)	1.00		1.00
Women	1.22 [0.27–5.58]	0.801	4.17 [0.43–40.38]	0.218
Comorbidities
Not present (Ref.)	1.00		1.00
Present	5.82 [0.50–67.09]	0.158	2.58 [0.22–29.72]	0.447
Vaccine type
Vector-based (Ref.)	1.00		n/a
RNA-based	0.43 [0.08–2.47]	0.347	n/a

References

1. Rucker, J.C. Oculomotor Disorders. Semin. Neurol.; 2007; 27, pp. 244-256. [DOI: https://dx.doi.org/10.1055/s-2007-979682] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/17577866]

2. Blumenfeld, H. Neuroanatomy through Clinical Cases; Sinauer: Sunderland, MA, USA, 2010.

3. Comer, R.M.; Dawson, E.; Plant, G.; Acheson, J.F.; Lee, J.P. Causes and outcomes for patients presenting with diplopia to an eye casualty department. Eye; 2007; 21, pp. 413-418. [DOI: https://dx.doi.org/10.1038/sj.eye.6702415] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/16732215]

4. Glover, K.; Mishra, D.; Singh, T.R.R. Epidemiology of Ocular Manifestations in Autoimmune Disease. Front. Immunol.; 2021; 12, 744396. [DOI: https://dx.doi.org/10.3389/fimmu.2021.744396]

5. Bhatti, M. 2022–2023 Basic and Clinical Science Course, Section 05: Neuro-Ophthalmology; San Francisco, CA, USA, 2021.

6. De Lott, L.B.; Kerber, K.A.; Lee, P.P.; Brown, D.L.; Burke, J.F. Diplopia-Related Ambulatory and Emergency Department Visits in the United States, 2003–2012. JAMA Ophthalmol.; 2017; 135, pp. 1339-1344. [DOI: https://dx.doi.org/10.1001/jamaophthalmol.2017.4508]

7. Franklin, R.Z. Diplopia resulting from paresis of third nerve caused by focal infection; a case report. Am. J. Optom. Arch. Am. Acad. Optom.; 1947; 24, pp. 609-610. [DOI: https://dx.doi.org/10.1097/00006324-194712000-00006] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/18917394]

8. Kedar, S.; Jayagopal, L.N.; Berger, J.R. Neurological and Ophthalmological Manifestations of Varicella Zoster Virus. J. Neuro-Ophthalmol.; 2019; 39, pp. 220-231. [DOI: https://dx.doi.org/10.1097/WNO.0000000000000721]

9. Rousseau, A.; Haigh, O.; Ksiaa, I.; Khairallah, M.; Labetoulle, M. Ocular Manifestations of West Nile Virus. Vaccines; 2020; 8, 641. [DOI: https://dx.doi.org/10.3390/vaccines8040641] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/33147758]

10. Sharp, A.; Santiago, L.; Dam, A.; Pereyra, C.; Mihailos, A. An Uncommon Diagnosis in a Child Presenting With Double Vision and Imbalance. Pediatr. Emerg. Care; 2019; 35, pp. e150-e151. [DOI: https://dx.doi.org/10.1097/PEC.0000000000001890] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/31335784]

11. Mueller, A.; Carvalho, H.; Montenegro, D. Herpes Zoster Ophthalmicus Complicated by Unilateral Ptosis and Abducens Nerve Palsy: A Case Report. Cureus; 2022; 14, e25311. [DOI: https://dx.doi.org/10.7759/cureus.25311]

12. Luís, M.E.V.; Hipólito-Fernandes, C.D.; Moniz, J.L.; Ferreira, J.T. The Neurotropic Varicella Zoster Virus: A Case of Isolated Abducens Nerve Palsy without Skin Rash in a Young Healthy Woman. Strabismus; 2021; 29, pp. 168-173. [DOI: https://dx.doi.org/10.1080/09273972.2021.1948073]

13. Davidson, S.I. Reports of ocular adverse reactions. Trans. Ophthalmol. Soc. UK; 1973; 93, pp. 495-510. [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/4526463]

14. Kurz, M. Two cases of brief diplopia following oral poliomyelitis vaccination in children. Wien. Med. Wochenschr.; 1966; 116, 135.

15. Goldstein, E.J.; Bell, D.J.; Gunson, R.N. Yellow fever vaccine-associated neurological disease: It is not just the silver generation at risk. BMJ Case Rep.; 2019; 12, e229558. [DOI: https://dx.doi.org/10.1136/bcr-2019-229558] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/31088820]

16. Grewal, D.S.; Zeid, J.L. Isolated abducens nerve palsy following neonatal hepatitis B vaccination. J. AAPOS; 2014; 18, pp. 75-76. [DOI: https://dx.doi.org/10.1016/j.jaapos.2013.09.012]

17. Plesner, A.-M.; Arlien-Soborg, P.; Herning, M. Neurological complications to vaccination against Japanese encephalitis. Eur. J. Neurol.; 1998; 5, pp. 479-485. [DOI: https://dx.doi.org/10.1046/j.1468-1331.1998.550479.x] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/10210877]

18. Gold, D.M.; Galetta, S.L. Neuro-ophthalmologic complications of coronavirus disease 2019 (COVID-19). Neurosci. Lett.; 2021; 742, 135531. [DOI: https://dx.doi.org/10.1016/j.neulet.2020.135531]

19. Luís, M.E.; Hipólito-Fernandes, D.; Mota, C.; Maleita, D.; Xavier, C.; Maio, T.; Cunha, J.P.; Ferreira, J.T. A Review of Neuro-Ophthalmological Manifestations of Human Coronavirus Infection. Eye Brain; 2020; 12, pp. 129-137. [DOI: https://dx.doi.org/10.2147/EB.S268828]

20. Petzold, A. Neuro-Ophthalmic Implications of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Related Infection and Vaccination. Asia-Pac. J. Ophthalmol.; 2022; 11, pp. 196-207. [DOI: https://dx.doi.org/10.1097/APO.0000000000000519]

21. Tisdale, A.K.; Chwalisz, B.K. Neuro-ophthalmic manifestations of coronavirus disease 19. Curr. Opin. Ophthalmol.; 2020; 31, pp. 489-494. [DOI: https://dx.doi.org/10.1097/ICU.0000000000000707]

22. Soltani, S.; Zandi, M.; Ahmadi, S.E.; Zarandi, B.; Hosseini, Z.; Akhavan Rezayat, S.; Abyadeh, M.; Pakzad, I.; Malekifar, P.; Pakzad, R. et al. Pooled Prevalence Estimate of Ocular Manifestations in COVID-19 Patients: A Systematic Review and Meta-Analysis. Iran. J. Med. Sci.; 2022; 47, pp. 2-14. [DOI: https://dx.doi.org/10.30476/ijms.2021.89475.2026]

23. Faucher, A.; Rey, P.-A.; Aguadisch, E.; Degos, B. Isolated post SARS-CoV-2 diplopia. J. Neurol.; 2020; 267, pp. 3128-3129. [DOI: https://dx.doi.org/10.1007/s00415-020-09987-x] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32533321]

24. Rzeszotarska, A.; Pawlak, M.; Anna, C.-C.; Szczapa-Jagustyn, J.; Kocięcki, J.; Siwiec-Siwiec-Prościńska, J.; Gotz-Więckowska, A. Diplopia and Optic Disc Edema as the Ocular Manifestations of COVID-19 in a Seven-Year-Old Child. Case Rep. Pediatr.; 2022; 2022, 8431692. [DOI: https://dx.doi.org/10.1155/2022/8431692] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/35726338]

25. Dinkin, M.; Gao, V.; Kahan, J.; Bobker, S.; Simonetto, M.; Wechsler, P.; Harpe, J.; Greer, C.; Mints, G.; Salama, G. et al. COVID-19 presenting with ophthalmoparesis from cranial nerve palsy. Neurology; 2020; 95, pp. 221-223. [DOI: https://dx.doi.org/10.1212/WNL.0000000000009700] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32358218]

26. Doblan, A.; Kaplama, M.E.; Ak, S.; Basmacı, N.; Tarini, E.Z.; Göktaş, Ş.E.; Güler, S.; Müderris, T. Cranial nerve involvement in COVID-19. Am. J. Otolaryngol.; 2021; 42, 102999. [DOI: https://dx.doi.org/10.1016/j.amjoto.2021.102999] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/33838359]

27. Haseeb, A.A.; Solyman, O.; Abushanab, M.M.; Obaia, A.S.A.; Elhusseiny, A.M. Ocular Complications Following Vaccination for COVID-19: A One-Year Retrospective. Vaccines; 2022; 10, 342. [DOI: https://dx.doi.org/10.3390/vaccines10020342]

28. Anilkumar, A.; Tan, E.; Cleaver, J.; Morrison, H.D. Isolated abducens nerve palsy in a patient with asymptomatic SARS-CoV-2 infection. J. Clin. Neurosci.; 2021; 89, pp. 65-67. [DOI: https://dx.doi.org/10.1016/j.jocn.2021.04.011]

29. Belghmaidi, S.; Nassih, H.; Boutgayout, S.; El Fakiri, K.; El Qadiry, R.; Hajji, I.; Bourrahouate, A.; Moutaouakil, A. Third Cranial Nerve Palsy Presenting with Unilateral Diplopia and Strabismus in a 24-Year-Old Woman with COVID-19. Am. J. Case Rep.; 2020; 21, e925897. [DOI: https://dx.doi.org/10.12659/AJCR.925897]

30. Elenga, N.; Martin, E.; Gerard, M.; Osei, L.; Rasouly, N. Unilateral diplopia and ptosis in a child with COVID-19 revealing third cranial nerve palsy. J. Infect. Public Health; 2021; 14, pp. 1198-1200. [DOI: https://dx.doi.org/10.1016/j.jiph.2021.08.007]

31. Prajwal, S.; Ikechukwu, A.; Bharosa, S.; Benjamin, M. Superior Divisional Palsy of the Oculomotor Nerve as a Presenting Sign of SARS-CoV-2 (COVID-19). J. Investig. Med. High Impact Case Rep.; 2022; 10, 23247096211058490. [DOI: https://dx.doi.org/10.1177/23247096211058490]

32. Ordás, C.M.; Villacieros-Álvarez, J.; Pastor-Vivas, A.-I.; Corrales-Benítez, Á. Concurrent tonic pupil and trochlear nerve palsy in COVID-19. J. NeuroVirol.; 2020; 26, pp. 970-972. [DOI: https://dx.doi.org/10.1007/s13365-020-00909-1]

33. Ben-David, G.S.; Halachmi-Eyal, O.; Shyriaiev, H.; Brikman, S.; Dori, G.; Briscoe, D. Diplopia from abducens nerve paresis as a presenting symptom of COVID-19: A case report and review of literature. Arq. Bras. Oftalmol.; 2021; 85, pp. 182-185. [DOI: https://dx.doi.org/10.5935/0004-2749.20220028] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/34431903]

34. Capponi, M.; Cinicola, B.L.; Brindisi, G.; Guido, C.A.; Torcé, M.C.; Zicari, A.M.; Spalice, A. COVID-19 and abducens nerve palsy in a 9-year-old girl—Case report. Ital. J. Pediatr.; 2022; 48, 102. [DOI: https://dx.doi.org/10.1186/s13052-022-01298-3] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/35717391]

35. Falcone, M.M.; Rong, A.J.; Salazar, H.; Redick, D.W.; Falcone, S.; Cavuoto, K.M. Acute abducens nerve palsy in a patient with the novel coronavirus disease (COVID-19). J. AAPOS; 2020; 24, pp. 216-217. [DOI: https://dx.doi.org/10.1016/j.jaapos.2020.06.001] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32592761]

36. Francis, J.E. Abducens Palsy and Anosmia Associated with COVID-19: A Case Report. Br. Ir. Orthopt. J.; 2021; 17, pp. 8-12. [DOI: https://dx.doi.org/10.22599/bioj.167]

37. Kubota, T.; Sugeno, N.; Sano, H.; Murakami, K.; Ikeda, K.; Misu, T.; Aoki, M. The Immediate Onset of Isolated and Unilateral Abducens Nerve Palsy Associated with COVID-19 Infection: A Case Report and Literature Review. Intern. Med.; 2022; 61, pp. 1761-1765. [DOI: https://dx.doi.org/10.2169/internalmedicine.9308-22]

38. Villalba, N.L.; Pierre, L.; Guerrero-Niño, J.; Jannot, X.; Andrès, E. Hearing Loss and Sixth Cranial Nerve Paresis after COVID-19. Eur. J. Case Rep. Intern. Med.; 2022; 9, 003221. [DOI: https://dx.doi.org/10.12890/2022_003221]

39. Manolopoulos, A.; Katsoulas, G.; Kintos, V.; Koutsokera, M.; Lykou, C.; Lapaki, K.-M.; Acquaviva, P.T. Isolated Abducens Nerve Palsy in a Patient with COVID-19: A Case Report and Literature Review. Neurologist; 2022; 27, pp. 139-142. [DOI: https://dx.doi.org/10.1097/NRL.0000000000000382]

40. de Medeiros, A.L.; Martins, T.; Kattah, M.; Soares, A.K.A.; Ventura, L.O.; Ventura, C.V.; Barros, E. Isolated abducens nerve palsy associated with coronavirus disease: An 8-month follow-up. Arq. Bras. Oftalmol.; 2021; 82, pp. 1-3. [DOI: https://dx.doi.org/10.5935/0004-2749.20220063]

41. Kakil, S.B.; Kosker, M. A Rare Side Effect of COVID-19 Vaccination: Abducens Nerve Palsy. Klin. Mon. Fur Augenheilkd.; 2022; 239, pp. 913-915. [DOI: https://dx.doi.org/10.1055/a-1814-4523]

42. Kubota, T.; Hasegawa, T.; Ikeda, K.; Aoki, M. Case Report: Isolated, unilateral oculomotor palsy with anti-GQ1b antibody following COVID-19 vaccination. F1000Research; 2021; 10, 1142. [DOI: https://dx.doi.org/10.12688/f1000research.74299.1]

43. Yvon, C.; Nee, D.; Chan, D.; Malhotra, R. Ophthalmoplegia associated with anti-GQ1b antibodies: Case report and review. Orbit; 2021; pp. 1-4. [DOI: https://dx.doi.org/10.1080/01676830.2021.1974495] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/34493154]

44. Yamakawa, M.; Nakahara, K.; Nakanishi, T.; Nomura, T.; Ueda, M. Miller Fisher Syndrome Following Vaccination against SARS-CoV-2. Intern. Med.; 2022; 61, pp. 1067-1069. [DOI: https://dx.doi.org/10.2169/internalmedicine.8851-21] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/35370249]

45. Odaka, M.; Yuki, N.; Hirata, K. Anti-GQ1b IgG antibody syndrome: Clinical and immunological range. J. Neurol. Neurosurg. Psychiatry; 2001; 70, pp. 50-55. [DOI: https://dx.doi.org/10.1136/jnnp.70.1.50] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/11118247]

46. Nagashima, T.; Koga, M.; Odaka, M.; Hirata, K.; Yuki, N. Clinical correlates of serum anti-GT1a IgG antibodies. J. Neurol. Sci.; 2004; 219, pp. 139-145. [DOI: https://dx.doi.org/10.1016/j.jns.2004.01.005] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/15050449]

47. Jarius, S.; Kleiter, I.; Ruprecht, K.; Asgari, N.; Pitarokoili, K.; Borisow, N.; Hümmert, M.W.; Trebst, C.; Pache, F.; Winkelmann, A. et al. MOG-IgG in NMO and related disorders: A multicenter study of 50 patients. Part 3: Brainstem involvement—Frequency, presentation and outcome. J. Neuroinflamm.; 2016; 13, 281. [DOI: https://dx.doi.org/10.1186/s12974-016-0719-z]

48. Manzano, G.S.; Salky, R.; Mateen, F.J.; Klawiter, E.C.; Chitnis, T.; Levy, M.; Matiello, M. Positive Predictive Value of MOG-IgG for Clinically Defined MOG-AD Within a Real-World Cohort. Front. Neurol.; 2022; 13, 947630. [DOI: https://dx.doi.org/10.3389/fneur.2022.947630]

49. Halpert, G.; Shoenfeld, Y. SARS-CoV-2, the autoimmune virus. Autoimmun. Rev.; 2020; 19, 102695. [DOI: https://dx.doi.org/10.1016/j.autrev.2020.102695]

50. Khamsi, R. Rogue antibodies could be driving severe COVID-19. Nature; 2021; 590, pp. 29-31. [DOI: https://dx.doi.org/10.1038/d41586-021-00149-1]

51. Mahgerefteh, J.S.; Oppenheimer, A.G.; Kay, M.D. Binocular Horizontal Diplopia Following mRNA-1273 Vaccine. J. Neuro-Ophthalmol.; 2022; [DOI: https://dx.doi.org/10.1097/WNO.0000000000001545]

52. Mungmungpuntipantip, R.; Wiwanitkit, V. Regarding Oculomotor Palsy After the Administration of the Messenger RNA-1273 Vaccine for SARS-CoV-2: Diplopia After the COVID-19 Vaccine. J. Neuro-Ophthalmol.; 2022; [DOI: https://dx.doi.org/10.1097/WNO.0000000000001558]

53. Pappaterra, M.C.; Rivera, E.J.; Oliver, A.L. Transient Oculomotor Palsy Following the Administration of the Messenger RNA-1273 Vaccine for SARS-CoV-2 Diplopia Following the COVID-19 Vaccine. J. Neuro-Ophthalmol.; 2021; [DOI: https://dx.doi.org/10.1097/WNO.0000000000001369] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/34369471]

54. Reshef, E.R.; Freitag, S.K.; Lee, N.G. Orbital Inflammation Following COVID-19 Vaccination. Ophthalmic Plast. Reconstr. Surg.; 2022; 38, pp. e67-e70. [DOI: https://dx.doi.org/10.1097/IOP.0000000000002161] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/35323144]

55. Dotan, A.; Muller, S.; Kanduc, D.; David, P.; Halpert, G.; Shoenfeld, Y. The SARS-CoV-2 as an instrumental trigger of autoimmunity. Autoimmun. Rev.; 2021; 20, 102792. [DOI: https://dx.doi.org/10.1016/j.autrev.2021.102792] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/33610751]

56. Zhou, Q.; Zhou, R.; Yang, H.; Yang, H. To Be or Not To Be Vaccinated: That Is a Question in Myasthenia Gravis. Front. Immunol.; 2021; 12, 733418. [DOI: https://dx.doi.org/10.3389/fimmu.2021.733418]

57. Lupica, A.; Di Stefano, V.; Iacono, S.; Pignolo, A.; Quartana, M.; Gagliardo, A.; Fierro, B.; Brighina, F. Impact of COVID-19 in AChR Myasthenia Gravis and the Safety of Vaccines: Data from an Italian Cohort. Neurol. Int.; 2022; 14, pp. 406-416. [DOI: https://dx.doi.org/10.3390/neurolint14020033]

58. Costa-Santos, C.; Neves, A.L.; Correia, R.; Santos, P.; Monteiro-Soares, M.; Freitas, A.; Ribeiro-Vaz, I.; Henriques, T.S.; Pereira Rodrigues, P.; Costa-Pereira, A. et al. COVID-19 surveillance data quality issues: A national consecutive case series. BMJ Open; 2021; 11, e047623. [DOI: https://dx.doi.org/10.1136/bmjopen-2020-047623]

59. Capak, K.; Kopal, R.; Benjak, T.; Cerovečki, I.; Draušnik, Ž.; Bucić, L.; Pristaš, I.; Curać, J. Surveillance system for coronavirus disease 2019 epidemiological parameters in Croatia. Croat. Med. J.; 2020; 61, pp. 481-482. [DOI: https://dx.doi.org/10.3325/cmj.2020.61.481]

60. Vukičević, D.; Polašek, O. Optimizing the diagnostic capacity for COVID-19 PCR testing for low resource and high demand settings: The development of information-dependent pooling protocol. J. Glob. Health; 2020; 10, 020515. [DOI: https://dx.doi.org/10.7189/jogh.10.020515]

61. Kristić, I.; Pehlić, M.; Pavlović, M.; Kolarić, B.; Kolčić, I.; Polašek, O. Coronavirus epidemic in Croatia: Case fatality decline during summer?. Croat. Med. J.; 2020; 61, pp. 501-507. [DOI: https://dx.doi.org/10.3325/cmj.2020.61.501]

62. Kapetanović, A.L.; Lukezić, M.; Pribisalić, A.; Poljak, D.; Polašek, O. Modeling the COVID-19 epidemic in Croatia: A comparison of three analytic approaches. Croat. Med. J.; 2022; 63, pp. 295-298. [DOI: https://dx.doi.org/10.3325/cmj.2022.63.295]

63. Primorac, D.; Perić, V.; Matišić, V.; Molnar, V.; Zadro, R.; Vince, A.; Lauc, G.; Polašek, O. Rapid COVID-19 Antigen Testing in Croatia: Risk Perception Plays an Important Role in the Epidemic Control. Front. Public Health; 2021; 9, 708907. [DOI: https://dx.doi.org/10.3389/fpubh.2021.708907] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/34386476]

64. Li, Y.C.; Bai, W.Z.; Hashikawa, T. The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients. J. Med. Virol.; 2020; 92, pp. 552-555. [DOI: https://dx.doi.org/10.1002/jmv.25728] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32104915]

65. Lotan, I.; Lydston, M.; Levy, M. Neuro-Ophthalmological Complications of the COVID-19 Vaccines: A Systematic Review. J. Neuro-Ophthalmol.; 2022; 42, pp. 154-162. [DOI: https://dx.doi.org/10.1097/WNO.0000000000001537] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/35427282]

66. Le Ng, X.; Betzler, B.K.; Testi, I.; Ho, S.L.; Tien, M.; Ngo, W.K.; Zierhut, M.; Chee, S.P.; Gupta, V.; Pavesio, E.C. et al. Ocular Adverse Events After COVID-19 Vaccination. Ocul. Immunol. Inflamm.; 2021; 29, pp. 1216-1224. [DOI: https://dx.doi.org/10.1080/09273948.2021.1976221]

67. Shafiq, A.; Salameh, M.A.; Laswi, I.; Mohammed, I.; Mhaimeed, O.; Mhaimeed, N.; Mhaimeed, N.; Paul, P.; Mushannen, M.; Elshafeey, A. et al. Neurological Immune-Related Adverse Events After COVID-19 Vaccination: A Systematic Review. J. Clin. Pharmacol.; 2022; 62, pp. 291-303. [DOI: https://dx.doi.org/10.1002/jcph.2017]

68. Wang, Z.; Liu, H.; Li, Y.; Luo, X.; Yang, N.; Lv, M.; Zhou, Q.; Li, Q.; Wang, L.; Zhao, J. et al. COVID-19 vaccine guidelines was numerous in quantity but many lack transparent reporting of methodological practices. J. Clin. Epidemiol.; 2022; 144, pp. 163-172. [DOI: https://dx.doi.org/10.1016/j.jclinepi.2021.12.015]

69. Costa-Font, J.; Asaria, M.; Mossialos, E. ‘Erring on the side of rare events’? A behavioural explanation for COVID-19 vaccine regulatory misalignment. J. Glob. Health; 2021; 11, 03080. [DOI: https://dx.doi.org/10.7189/jogh.11.03080]

70. Menni, C.; Klaser, K.; May, A.; Polidori, L.; Capdevila, J.; Louca, P.; Sudre, C.H.; Nguyen, L.H.; Drew, D.A.; Merino, J. et al. Vaccine side-effects and SARS-CoV-2 infection after vaccination in users of the COVID Symptom Study app in the UK: A prospective observational study. Lancet Infect. Dis.; 2021; 21, pp. 939-949. [DOI: https://dx.doi.org/10.1016/S1473-3099(21)00224-3]

71. Chen, X.; Li, X.; Li, H.; Li, M.; Gong, S. Ocular Adverse Events after Inactivated COVID-19 Vaccination in Xiamen. Vaccines; 2022; 10, 482. [DOI: https://dx.doi.org/10.3390/vaccines10030482]

72. Li, Z.; Hu, F.; Li, Q.; Wang, S.; Chen, C.; Zhang, Y.; Mao, Y.; Shi, X.; Zhou, H.; Cao, X. et al. Ocular Adverse Events after Inactivated COVID-19 Vaccination. Vaccines; 2022; 10, 918. [DOI: https://dx.doi.org/10.3390/vaccines10060918]

73. Ren, J.; Zhang, T.; Li, X.; Liu, G. Ocular Inflammatory Reactions following an Inactivated SARS-CoV-2 Vaccine: A Four Case Series. Ocul. Immunol. Inflamm.; 2022; pp. 1-6. [DOI: https://dx.doi.org/10.1080/09273948.2022.2093754] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/35819841]

74. Nyankerh, C.N.A.; Boateng, A.K.; Appah, M. Ocular Complications after COVID-19 Vaccination, Vaccine Adverse Event Reporting System. Vaccines; 2022; 10, 941. [DOI: https://dx.doi.org/10.3390/vaccines10060941] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/35746549]

75. Choi, M.; Seo, M.-H.; Choi, K.-E.; Lee, S.; Choi, B.; Yun, C.; Kim, S.-W.; Kim, Y.Y. Vision-Threatening Ocular Adverse Events after Vaccination against Coronavirus Disease 2019. J. Clin. Med.; 2022; 11, 3318. [DOI: https://dx.doi.org/10.3390/jcm11123318] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/35743388]

76. Remmel, A. Why is it so hard to investigate the rare side effects of COVID vaccines?. Nature; 2021; [DOI: https://dx.doi.org/10.1038/d41586-021-00880-9] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/33795861]

77. Dörks, M.; Jobski, K.; Hoffmann, F.; Douros, A. Global COVID-19 pandemic and reporting behavior—An analysis of the Food and Drug Administration adverse events reporting system. Pharmacoepidemiol. Drug Saf.; 2021; 30, pp. 707-715. [DOI: https://dx.doi.org/10.1002/pds.5217]

78. Eleiwa, T.K.; Gaier, E.D.; Haseeb, A.; ElSheikh, R.H.; Sallam, A.B.; Elhusseiny, A.M. Adverse Ocular Events following COVID-19 Vaccination. Inflamm. Res.; 2021; 70, pp. 1005-1009. [DOI: https://dx.doi.org/10.1007/s00011-021-01506-6]