Various studies have been published on neuro-ophthalmologic adverse events associated with COVID-19; however, several of these involved case reports, and analytical studies have been limited in confirming accurate associations by their small sample sizes. Our study was a nationwide, population-based study, which facilitated further confirmation of the associations observed in previous studies. For COVID-19 infection and vaccination, the incidence rate and risk of the majority of neuro-ophthalmic adverse events were low, showing minimal differences compared to the control group. For instance, no statistically significant difference was observed between COVID-19 infection, vaccination, and control groups for optic neuritis, in agreement with a recent paper that found no association between optic neuritis and vaccination.
30 However, some of the adverse events exhibited a higher incidence in the infection or vaccination groups than in the control group, with ptosis and GBS/MFS showing a statistically significant increase in incidence when considering the differences in incidence rates and the number of events.
Ptosis had a higher incidence rate in the vaccination, but not in the infection group, than in the control group. Particularly, its incidence rate was higher after 60 d than within 60 d (
Fig. 2I and
Supplementary Fig. S2I). Ptosis is commonly induced by third nerve palsy. However, this risk, as indicated by an HR <1 in the infection and vaccination groups, was not higher than that in the control group (
Fig. 2D and
Supplementary Fig. S2D).
We also assessed MG as another condition that can lead to ptosis. MG is an autoimmune disease where antibodies against the nicotinic acetylcholine receptors in the neuromuscular junction are produced, inducing fatigable muscle weakness, such as ptosis.
18,31,32 Occurrence of MG after COVID-19 infection or vaccination has been reported in several studies,
18,27–29,31 but the small sample size in these studies hampered conclusions of a direct correlation. We found no statistically significant association between COVID-19 infection and MG during the early phase, while during the late phase, COVID-19 infection was associated with a reduced MG risk (
Supplementary Fig. S5). It is widely acknowledged that viral or bacterial infections can trigger myasthenic crises in individuals with pre-existing MG. However, no clear consensus exists on whether MG incidence is higher in COVID-19 patients.
18 Similar to previous studies on the relationship between general infections and MG, we found no association between COVID-19 infection and MG onset. Similar to the infection group, the MG incidence rate was not significantly increased in the vaccination group.
Given the above, the increased ptosis frequency in this study needs to be interpreted differently. The order of the cumulative incidence of ptosis in this study was vaccination group, infection group, and control group (
Supplementary Fig. S1I), consistent with the order of mean age among these groups (
Table). The prevalence of underlying diseases also showed significant increases, following the same order as age, across the three groups. Ptosis is generally more prevalent in older adults; therefore the difference in incidence is likely due to age rather than COVID-19, as with other comorbidities. Additionally, patients with pre-existing ptosis may have become aware of their condition after COVID-19 infection or vaccination. Therefore additional studies are necessary to clarify the association between ptosis and COVID-19 infection.
GBS/MFS also showed a higher incidence rate in COVID-19 patients. Several case reports and studies on GBS after COVID-19 infection and vaccination have been published.
33–36 MFS is a GBS subtype. GBS is an immune-mediated postinfectious syndrome that affects peripheral nerves and their roots. This is a consequence of molecular mimicry caused by viral or bacterial infection, leading to the production of anti-ganglioside antibodies that attack proteins expressed on the axon membrane. A significant association is suggested to exist between COVID-19 and GBS, including MFS, given the disease epidemiology and symptom pathogenesis.
35 Similarly, we found a significantly higher HR and incidence rate in the infection than in the control group, with incidence rates of 13.1 per 100,000 person-years within 60 days. These results were higher than the previously reported incidence rates of GBS (1.1–1.8 per 100,000 person-years).
37 Considering that MFS is a GBS subtype, this incidence is extremely high. This suggests that the COVID-19 infection influences MFS development, as suggested by several previous studies, and is predictable considering MFS pathogenesis. Furthermore, in this study, significant results were observed only in the early phase, with no significant differences in the late phase. This aligns with the typical onset of GBS/MFS, which usually occurs within four weeks after the predisposing infection. This was also evident in the cumulative incidence rate, which exhibited a significant increase until approximately 4 weeks, after which it remained relatively stable (
Supplementary Fig. S1L). Therefore the risk factors for GBS/MFS in patients with COVID-19 (age [HR =1.04 {95% CI, 1.00–1.08};
P = 0.043] and hypothyroidism history [HR = 4.22 {95% CI, 1.12–15.90}
P = 0.033]) identified in the early phase of follow-up are likely to be valid.
Throughout the entire follow-up period, the vaccination and control groups showed no significant differences in GBS/MFS (
Fig. 2L and
Supplementary Fig. S2L). In the sub-analyses based on vaccine types, during the early phase, no vaccines showed a significant difference compared to the control group. In the late phase, only ChAdOx1 exhibited a significant difference compared to the control group, whereas the other vaccines showed no significant differences. Although ChAdOx1 showed significant results in the late phase, considering GBS/MFS onset, the association with vaccination is unlikely to be significant. A recent report on the association between COVID-19 vaccines and GBS using the US vaccine Adverse Event Reporting System
38 confirmed findings similar to that of our study. In that report, the portion of Ad26.COV2.S among the administered vaccines was only 3.7%; however, the GBS incidence was 27.8% in all cases, compared to 35.3% and 36.3% for BNT162b2 and mRNA-1273, respectively. This represents a nine- to 12-fold increase in reported GBS after Ad26.COV2.S as compared to BNT162b2 or mRNA-1273. Compared to the expected incidence, the difference between the BNT162b2 and mRNA-1273 vaccines was insignificant, whereas a two- to threefold higher incidence was found in patients administered the Ad26.COV2.S than in those administered other vaccines.
38 The aforementioned study showed a significant association of GBS with Ad26.COV2.S. This was in contrast to our findings, which is likely because of the significantly lower number of patients who received mRNA-1273 and Ad26.COV2.S in our study than those who received other vaccines. As MFS is a GBS subtype and has similar pathogenesis, it would show similar results to those of GBS.
The strengths of this study are its large sample size and nationwide estimates representing the entire Korean population. This enabled us to focus on identifying the incidence of individual diseases, rather than relying on previously published case reports and studies involving clinical patterns. However, this study has several limitations. First, there are some limitations inherent to the data per se. Analyzing information not registered in the database was impossible. For example, the clinical characteristics of neuro-ophthalmologic adverse events in patients with COVID-19 cannot be determined because the clinical presentation of each patient is not registered in the database. Additionally, the ICD-10 codes for identifying diagnoses in this study were not fully representative of the adverse events. We attempted using the ICD-10 codes comprising a single disease as much as possible; however, in some cases, such as in GBS/MFS, individual GBS subtypes are grouped under a single ICD-10 code and were unavoidably included. Furthermore, the baseline characteristics of each group were heterogeneous, largely due to the way we defined the control group and the vaccine supply of South Korea. In principle, the control group should consist of individuals who are uninfected and simultaneously unvaccinated. However, because >98% of adults in South Korea have been vaccinated, a potential for bias existed during the analysis because of the limited sample size of the control group. Therefore, in our study, the control group comprised individuals who were not infected at the outset but who subsequently received the vaccine, which led to a relatively higher proportion of younger than older patients, leading to a substantial difference in age among groups. Additionally, the shortage in the global vaccine supply in the early stages of vaccine distribution led to more relatively older patients receiving vaccinations early during the pandemic course, leading to a higher proportion of older patients than younger patients in the vaccination group. Multivariate Cox analysis, using all the demographic variables included in this study, was conducted to address these biases, and the results obtained remained consistent with those obtained from the pre-adjusted analysis. However, it is possible that the Cox analysis may not have been adequately adjusted. Therefore conducting additional research using cohort matching could provide a more definitive confirmation of the results. Moreover, ChAdOx1 was distributed relatively earlier than the other vaccines at the beginning of the pandemic and was mainly distributed to military personnel in South Korea. Therefore groups administered the ChAdOx1 vaccine were younger and more male dominated than those administered other vaccines. Finally, this study was conducted exclusively in South Korea with a relatively homogenous population; therefore our findings may not be generalizable to other populations worldwide.
In conclusion, we found no association between neuro-ophthalmic adverse events other than ptosis and GBS/MFS with COVID-19 infection or COVID-19 vaccination. However, we found a higher incidence rate of ptosis in patients who were vaccinated against COVID-19 than in those without vaccination. Additionally, patients diagnosed with COVID-19 had significantly higher incidence rates of GBS/MFS. Although the COVID-19 pandemic is being brought under control, several patients still suffer from infection and vaccine sequelae. Our findings may help clinicians to diagnose and treat the adverse events related to COVID-19 infection and vaccination.