Discussion
COVID-19 vaccine-associated ophthalmic adverse effects have been reported in recent literature. These adverse effects include uveitis, episcleritis and scleritis, optic and cranial neuropathies, intraretinal changes and orbital inflammation including acute-onset dacryoadenitis, myositis and THS [
2,
4,
8,
12‐
18]. Symptom onset ranged from 9 h up to 42 days post-vaccination [
1,
4,
6,
7,
19]. To the best of our knowledge, this case series represents the third reported occurrence of THS and two additional reports of orbital myositis following the COVID-19 vaccine (Comirnaty, Pfizer-BioNTech) [
4,
6,
8,
19]. Table
1 summarises the cases of this present study and those reported in the literature.
Table 1
Summary table of cases of COVID-19 vaccination-associated orbital inflammation. Cases 1–3 represent the present study’s cases.
1 | F/58 | + | BNT162b2 mRNA, Pfizer/BioNTech | 3 | 14d | Left | + | | + | + | | | | + | | | Orbital apex extending to SOF and cavernous sinus |
2 | M/46 | | BNT162b2 mRNA, Pfizer/BioNTech | 1 | 10d | Right | + | + | | | | | Episcleritis | | + (Bilateral) | | |
3 | F/61 | + | BNT162b2 mRNA, Pfizer/BioNTech | 2 and 4 | 1d and 4d | Left | + | | + | + | + | | | + | + | | |
| M/68 | | BNT162b2 mRNA, Pfizer/BioNTech | 2 | 4d | Left | + | | + | + | + | | | | + | | |
| F/33 | + * | mRNA-1273, Moderna | 2 | 1d | Left | + | + | + | + | + | | Myalgia, headache | | + | | |
| M/13 | + | BNT162b2 mRNA, Pfizer/BioNTech | 1 | 1d | Left | + | + | + | | + | | | + | | + | |
| F/39 | + # | mRNA-1273, Moderna | 1 | 24 h | Bilateral | + | + | + | | + | + | | | + | | |
| M/14 | | BNT162b2 mRNA, Pfizer/BioNTech | 1 | 9 h | Right | + | + | + | + | + | | | + | + | + | |
| F/40 | | BNT162b2 mRNA, Pfizer/BioNTech | 1 | 7d | Left | + | | | | + | | | | + | + | |
| F/65 | | BNT162b2 mRNA, Pfizer/BioNTech | 1 and 2 | 2d | Bilateral | + | + | | | + | Right-side | | + | + | | |
| M/45 | | mRNA-1273, Moderna | 1 | 5d | Left | | | + | + | | + | Ptosis, headache | | | | Orbital apex, extending to cavernous sinus |
| F/76 | | CoronaVac/Sinovac | 2 | 35d | Right | | | + | + | | | Preceding headache, photophobia, phonophobia; ptosis | | | | Cavernous sinus |
| F/64 | | BNT162b2 mRNA, Pfizer/BioNTech | 2 | 5d | Right | + | + | + | + | + | | Scleritis | | + | | |
| F/45 | | mRNA-1273, Moderna | 1 | 6d | Left | | | + | + | + | | Asthenopia when reading | | + | | |
Tolosa–Hunt syndrome has recently been described following both COVID-19 infections and vaccinations [
4,
5]. Chuang et al. first reported THS in a 45-year-old male, 7 days after his first dose of COVID-19 vaccination (mRNA-1273) [
4]. Contrast-enhanced MRI orbits revealed bilateral perineural enhancement surrounding the optic nerve sheaths (left greater than right), with poorly-defined enhancement in the left orbital apex extending into the cavernous sinus [
4]. Pedro et al. similarly reported occurrence of THS in a 76-year-old female after completing both doses of the CoronaVac/Sinovac COVID-19 vaccination scheme (45 days between the first and second doses). The patient initially experienced multiple episodes of severe headache, phonophobia, photophobia and otalgia, shortly after the first dose and worsening after the second dose. Symptoms of THS, including painful diplopia with incomplete palsy of the right cranial nerves III, IV and VI, occurred 35 days after the second dose [
19]. In contrast with the previous two reported cases, onset of THS in our patient only occurred after the third (booster) vaccination with no adverse effects after the initial two doses.
Inflammation following COVID-19 vaccination has been reported to affect various orbital structures, including six cases of isolated myositis, two cases of diffuse orbital inflammation (lacrimal gland, extraocular muscle, and orbital fat involvement) and one case of isolated dacryoadenitis (Table
1) [
6‐
11]. Within the literature and our cases, orbital inflammation is primarily unilateral, predominantly involve the extraocular muscles and orbital fat, while lacrimal gland is less commonly involved. Acute bilateral orbital myositis was reported 24 h after administration of mRNA-1273 (Moderna) vaccine [
6]. Additionally, Gencoglu and Mangan described a case of orbital inflammation, affecting the lateral and superior recti, and lacrimal gland, following the first dose of COVID-19 vaccination (Comirnaty, Pfizer-BioNTech) 1 week prior [
10]. Orbital myositis may also present with scleritis or episcleritis, as described by Savino et al. and within our case (Case 2) [
11]. Reshef et al. described three patients with orbital involvement, ranging from the EOM, lacrimal gland and intraconal fat, all occurring within 1 week of vaccination [
8]. Meanwhile, in our case of orbital myositis, onset of symptoms was observed 10 days following the first dose. Grunewald et al. have reported bilateral orbital inflammation involving the EOM and orbital fat occurring approximately 2 days after the first COVID-19 vaccination (Comirnaty, Pfizer-BioNTech), with exacerbation of the right-sided symptoms occurring after the second dose [
9]. Similarly, exacerbation of orbital inflammation coincided with administration of the fourth COVID-19 vaccination in Case 3. Finally, Murphy et al. described acute-onset dacryoadenitis occurring 9 h following the first dose of COVID-19 vaccination (Comirnaty, Pfizer-BioNTech) [
7].
The duration between COVID-19 vaccination and symptom onset of orbital inflammation is variable. In the two reported cases of THS, ocular symptoms occurred 5 and 35 days after vaccination, respectively [
4,
19]. Meanwhile, our patients developed symptoms 1–14 days after their vaccination. Other cases of orbital inflammation have generally had more acute onset, ranging from 9 h to 4 days after vaccination [
6‐
8]. Nevertheless, late-onset adverse effects, up to 42 days following COVID-19 vaccination, with signs of intraocular inflammation, have been reported; however, delayed presentation could not be excluded [
3]. In this particular case of THS, we postulate that repeated exposure to an immunogenic stimulus, such as the COVID-19 vaccination, may have precipitated orbital inflammation following the third (booster) dose. However, we cannot comment on the causality of Tolosa–Hunt syndrome in this case, and it remains entirely plausible that it occurred as a vaccination-independent phenomenon, as evident by a number of orbital inflammation cases presenting after the first dose of COVID-19 vaccination.
The majority of patients with uveitis and scleritis occurring after a COVID-19 vaccination had previous episodes of an ocular inflammatory event [
13]. This has also been reported in the orbital inflammation literature [
20]. Reshef et al. reported two patients with prior episodes of non-specific orbital inflammation. One patient had recurrent myositis triggered by upper respiratory tract infections, while the other had previously experienced orbital inflammation following the influenza vaccine 1 year prior [
8]. In our patient with THS, however, a different manifestation of orbital inflammation was observed from the initial episode of bilateral idiopathic dacryoadenitis 6 years prior. Our patient in Case 2 had a previous history of idiopathic episcleritis. Meanwhile, Case 3 had recurrent episodes of steroid-responsive biopsy-confirmed non-specific dacryoadenitis, although there was a suspicion of an underlying granulomatous disease process. Thus, it remains plausible that certain stimuli, such as the COVID-19 vaccine, may incite inflammation in patients with a tendency for both non-specific and specific causes of orbital inflammation. Patients with prior orbital inflammation may have an autoimmune predisposition to certain stimuli such as the COVID-19 vaccination, although a statistically significant correlation has not been observed [
21]. Additionally, both the COVID-19 infection and other vaccines for influenza and shingles have also been associated with occurrence of orbital inflammation [
22‐
26]. Manifestations of these
de novo cases of orbital inflammation included sudden-onset unilateral ptosis and orbital myositis, bilateral orbital inflammation and orbital myositis with posterior scleritis [
22‐
26].
Several hypotheses, primarily revolving around an immunological process, have been proposed regarding the pathogenesis of COVID-19 vaccine-associated orbital inflammation [
6,
8]. Our case series, along with eight other reported cases, have been associated with an mRNA-based COVID-19 vaccine. It has been postulated that uncoated mRNA molecules are pro-inflammatory in the extracellular compartment and degradation of the coated mRNA vaccine, may incite inflammation [
27]. Other proposed mechanisms implicate the vaccine’s excipient components [
6,
28]. We acknowledge that with mass administration of the COVID-19 vaccination programme in Australia, it remains plausible that orbital inflammation may only be coincidentally associated with recent vaccination.
Management of COVID-19 vaccine-associated orbital inflammation included a course of intravenous and/or oral corticosteroid, or oral nonsteroidal anti-inflammatories (NSAIDs) [
4,
6‐
11]. Case 2 had complete resolution with conservative measures alone. Depending on the severity of inflammation and status of optic nerve function, corticosteroid regimens included 1-g intravenous (IV) methylprednisolone for 3 days, followed by an oral corticosteroid taper over 6 weeks, or 60-mg oral prednisone which was tapered over 1 month [
4,
6‐
8]. Case reports have also described the use of prophylactic corticosteroids before subsequent COVID-19 vaccinations, with regimens describing continuing the tapering dose from the initial episode at 20 mg prior to the second vaccination; or initiating a 3-day course of 60-mg oral prednisolone followed by a 10-mg taper every 3 days, with no further episodes of orbital inflammation.
In conclusion, we reported three cases of orbital inflammation occurring 1–14 days following a COVID-19 vaccination (Comirnaty, Pfizer-BioNTech). The clinical manifestations included THS and isolated orbital myositis, and these cases add to a steadily growing body of the literature of COVID-19 vaccine-associated orbital inflammation. The causal association cannot be determined but recognition of this entity is important in addition to consideration of future vaccinations for such patients.
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