Neuro-Ophthalmic Complications of COVID-19 Infection and Vaccination

Abstract

The COVID-19 pandemic has led to the identification of new disease phenotypes associated with infection by the SARS-CoV-2 virus. This includes multiple neuro-ophthalmological sequelae, which have been associated with COVID-19 infection and administration of COVID-19 vaccines. Some of these associations have a plausible pathophysiological link to the infection or vaccination but true causation has yet to be established. We review the literature for associations reported between COVID-19 infection or vaccination and neuro-ophthalmic sequelae and review the potential pathophysiological processes that may underlie these associations.

Key points

• •COVID-19 infection and vaccination have been associated with neuro-ophthalmic complications but causation has not been firmly established.
• •Neuro-ophthalmic manifestations post-COVID-19 infection and vaccination are uncommon and have a good prognosis in most cases.
• •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.
• •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.
• •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 more than a billion confirmed cases of COVID-19 infection, and more than 6 million deaths worldwide have occurred [1]. 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, more than 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 [[2], [3], [4]]. However, new presentations of autoimmune conditions have been associated with COVID-19 vaccination [5]. The postinfection and postvaccine 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. Moreover, 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 are 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 cutoff 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 [6].

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 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 [7,8]. Most of the cases were unilateral with variable onset ranging between 1 and 45 days postinfection [[9], [10], [11]]. All patients received (1 g/d) of intravenous methylprednisolone (IVMP) followed by oral prednisone taper [7]. Additionally, myelin oligodendrocyte glycoprotein (MOG)-related ON was found to have a favorable visual outcome following IVMP with vision better than 20/200 in all patients [11]. In a systematic review, only 3 cases of neuro-myelitis optica (NMO) Aquaporin 4 IgG-positive ON were identified [12]. Two were men, aged 70 years and 25 years, respectively, and one 7.5-year-old girl. They all presented within a month of their COVID-19 infection. Treatment with steroids, intravenous immunoglobulin (IVIG), plasma exchange (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 [12].

Post-COVID-19 vaccination

ON post-COVID-19 vaccination is the most commonly reported neuro-ophthalmic association [13], with 55 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 within 3 weeks from the administration of the vaccine in most patients. This is 1 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 prepandemic ON. Unilateral involvement was more common than bilateral. MOG-positive ON was 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 [14,15]. 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 patients, and a few patients received high doses of oral steroids, whereas 7 patients did not receive any steroids. PLEX was used in 6 patients 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 14 cases of idiopathic ON post-COVID-19 vaccination [[16], [17], [18], [19], [20], [21], [22], [23]], again most cases were in women (10 cases) half with unilateral involvement, and age ranged from 19 to 67 years. Vision changes were reported from hours to 3 weeks after BioNTech/Pfizer mRNA-vaccine BNT162b2, AstraZeneca ChAdOx1, Janssen (Johnson & Johnson), Covishield, CoronaVac-Sinovac Life, and Moderna mRNA-1273 vaccines. Optic disc swelling was noted in 8 patients on examination, and the presenting visual acuity of less than 20/200 was noted in 4 patients. 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 [23].

MOG-ON was reported to comprise approximately 5% of ON cases prepandemic [15], with an increased rate of MOG-ON since the start of the pandemic [5,13,[24], [25], [26], [27]]. 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 and 66 years with most (7 cases) having unilateral involvement. Half had a visual acuity of less than 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 to 5 days, followed by oral steroids. In 4 patients, presenting with poor vision or bilateral involvement, PLEX was initiated. Only 1 patient had a spontaneous resolution of vision with no intervention.

NMO-ON was reported in (3%) of patients prepandemic, and it remained an uncommon cause of ON postvaccination [15]. Case reports of NMO-ON postvaccination exists and include cases after mRNA vaccination: a 43-year-old woman and a 31-year-old woman, both with unilateral involvement, one with complete recovery of her vision after receiving IVMP (1 g/d) for 10 days and the other with no visual recovery after receiving IVMP (1 g/d) for 5 days followed by 5 sessions of PLEX [28,29].

Giant cell arteritis

Post-COVID-19 infection

A noticeable increase in GCA cases occurred during the COVID-19 pandemic, a report by Lecler and colleagues, observed an increase of 70% from prepandemic [30]. Subsequently, higher rates of ocular involvement were seen with GCA during the pandemic [31,32]. 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 and colleagues, found that they both share the clinical features of headache, fever, elevated C-reactive protein (CRP), and cough. Clinical manifestations that can aid in the differentiation of GCA would be jaw claudication, visual loss, platelet count, and lymphocyte count [33].

Post-COVID-19 vaccination

Three case reports exist of GCA presenting with arteritic anterior ischemic optic neuropathy after COVID-19 vaccination [[34], [35], [36]]: 2 in 87-year-old and 79-year-old women and 1 in a 68-year-old man. Two cases were after BioNTech/Pfizer mRNA-vaccine BNT162b2 vaccine and 1 after the AstraZeneca ChAdOx1 vaccine. They all presented within 5 days of receiving the vaccine and all had bilateral involvement. The visual acuity was less than 20/200 in at least 1 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 1 of the inflammatory markers was high, ESR in 2 cases and CRP in all 3 cases. A temporal artery biopsy was positive in 2 of the patients, and for one patient no information was provided about the biopsy. All patients were treated with high-dose IVMP (1 g/d) for 3–4 days followed by oral prednisolone [[34], [35], [36]], 1 patient subsequently received tocilizumab following a relapse 3 months after the initial presentation [34].

In both post-COVID-19 and postvaccination cases no proved causation exists and the time lapse for the postvaccination 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.

Nonarteritic anterior ischemic optic neuropathy

Post-COVID-19 infection

The relationship of COVID-19 and nonarteritic anterior ischemic optic neuropathy (NA-AION) is unknown [37]. NA-AION has been described in 6 case reports in association with COVID-19 infection [[38], [39], [40], [41], [42]]. Patients in these reports were aged older than 40 years and presented with acute painless unilateral or bilateral (2/6) altitudinal vision loss, which mainly was noted on awakening (4/6 patients). The onset of visual symptoms ranged from 1 to 4 weeks after COVID-19 infection except in 1 patient where visual symptoms preceded COVID-19 symptoms [41]. All cases demonstrated visual field defect on confrontational testing and Humphrey’s visual field analysis [38,39].

Post-COVID-19 vaccination

NA-AION post-COVID-19 vaccination has rarely been reported [[43], [44], [45], [46], [47], [48]]. 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 within 15 days from the vaccination (1–15 days). Most of the patients were aged older than 50 years and had 1 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 ON. IV or PO steroids were administered in some cases, either for the suspicion of ON or GCA. 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 to 20/100 to 1 eccentrically after 6 weeks [48]. This case report does not 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 [49]. Of those, 85% (11/13) were found to have high opening pressure (>200mmH2O), and more than half (7/13) were greater than (250mmH2O) with normal composition and were diagnosed with idiopathic intracranial hypertension (IIH). Imaging of the brain was not significant except in 1 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 3 patients.

Cerebral venous sinus thrombosis (CVST) 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 and colleagues 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 [50]. 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, and endovascular transverse sinus thrombectomy, her vision deteriorated to no light perception.

Post-COVID-19 vaccination

There have been 2 published case reports of papilledema in the setting of COVID-19 vaccination-associated IIH [51,52]. 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 (750 mg) twice daily and torsemide (5 mg) once daily, and the other was given pulse IVMP (500 mg daily) for 5 days and oral acetazolamide (250 mg) 3 times a day. After 3 months, the symptoms and papilledema had completely resolved in both cases [51,52].

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 [53,54]. The group most at risk was women aged under 60 years [54]. 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) [53]. In a meta-analysis of 144 patients up to 80% had an accompanying thrombocytopenia and hypofibrinogenemia with a positive PF4 antibodies [54]. Most patients present to the emergency department and are treated with nonheparin anticoagulants. The mortality rate from CVST is as high as 40%, therefore, timely diagnosis is key [53].

Efferent neuro-ophthalmic complications

Ocular motility disorders

Diplopia is one of the more common symptoms reported post-COVID-19 infection and vaccination. Underlying pathologic conditions vary from cranial nerve palsy and Miller Fisher syndrome (MFS) to neuromuscular junction disorders such as myasthenia gravis (MG), and muscular pathologic conditions such as 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 [55]. Isolated cranial neuropathies were more prevalent than multiple cranial neuropathies. Unilateral involvement is more common than bilateral involvement, although 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 postvaccination 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 [[56], [57], [58], [59], [60], [61], [62], [63], [64]]. The onset of diplopia usually was from 1 to 7 days; it has been reported postvaccination with BioNTech/Pfizer mRNA-vaccine BNT162b2, Moderna mRNA-1273, Covishield, AstraZeneca ChAdOx1, and Sinopharm. Age ranged from 23 to 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 [63]. Two-thirds had full spontaneous recovery of symptoms after 2 months, including those with brain imaging abnormalities. Steroids were used in 2 out of 9 patients: 1 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 and colleagues 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 [65]. Another case by Shalabi and colleagues 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 [66]. In both cases, an extensive workup was done, including brain imaging with contrast, infectious and inflammatory laboratory 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 [65,66]. As with NA-AION, improvement after steroids does not necessarily confirm a treatment affect because 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 [[67], [68], [69]]. A proposed mechanism by which MFS develops is through an immune-mediated postinfectious process [70]. This is supported by the incubation period, the positive response to IVIG, and the presence of antiganglioside antibodies in 20% of reported cases [67,70].

Post-COVID-19 vaccination

The onset of symptoms in MFS postvaccination ranged from (7 to 18 days). It has been reported after administering 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 [[71], [72], [73], [74], [75], [76], [77], [78]]. In 5 out of 7 cases, evidence existed of albuminocytological dissociation in the cerebrospinal fluid sample analysis, which is defined as elevated proteins without pleocytosis. In 3 out of 7 antiganglioside antibodies such as anti-GQ1b antibody were positive [74,78]. Patients were treated with IVIG with recovery taking from weeks to months. One patient received physiotherapy only with reported full spontaneous recovery at 10-week follow-up [75].

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 [[79], [80], [81], [82], [83]]. The incidence of MG was found to be marginally higher in patients with COVID-19 infection compared with general population (0.087% and 0.07%, respectively) [84]. Age has ranged from 6 to 65 years old. Patients complained mostly of diplopia and fatigable ptosis with limitations of ocular motility noted on examination. Treatment composed 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, whereas others had only partial recovery [79,83]. All patients had elevated titers of antiacetylcholine receptor (AchR) 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 as a COVID-19 sequela [80,81].

Post-COVID-19 vaccination

New onset or exacerbation of ocular or generalized MG has been reported after administering BioNTech/Pfizer mRNA-vaccine BNT162b2, Moderna mRNA-1273, and AstraZeneca ChAdOx1 vaccines [85,86]. 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 aged older than 60 years [[87], [88], [89], [90], [91], [92], [93], [94]]. Exacerbation of preexisting MG postvaccine is thought to be from 1% to 15% [87]. Ocular MG cases presented with intermittent fatigable ptosis and diplopia [88,90,92,94]. In some of the cases, associated symptoms occurred such as fatigue and weakness, myalgia, dysarthria, dysphagia, and head drop [87,89,91,93]. In 8 of the 11 patients AchR antibodies was positive but none was positive for anti–muscle-specific kinase (MuSK) antibodies [85,87,88,90,91]. 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 [85,93,94]. Computed tomography of the chest was negative except for 1 patient with mild thymic hyperplasia; interestingly, this case was double seronegative [93]. The treatment of choice was pyridostigmine alone [85,87,93,94] or combined with steroids [85,[87], [88], [89],91,92] 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 [85].

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 and colleagues, 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 [95]. TED post-COVID-19 vaccination was documented after BioNTech/Pfizer mRNA-vaccine BNT162b2 and Moderna mRNA-1273 vaccine, 2 were new onset, and 2 were reactivation [96,97]. Patients were middle-aged women with no history of smoking. Two were previously treated GD patients, 1 was a treated Hashimoto thyroiditis patient, and 1 patient had no history of underlying thyroid dysfunction [96,97]. 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. Fortunately, none had any afferent issues on the examination such as compressive optic neuropathy. All showed evidence of thyroid dysfunction on laboratory workup except in 1 case [96,97]. 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 1 patient [97].

IOIS can mimic the presentation of TED, and 1 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 [98]. 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 2 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 2 cases are identified in the literature with long-term pupillary abnormalities following COVID-19 infection [99,100]. Both patients experienced visual dysfunction with evidence of anisocoria 3 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 [99]. 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 [100].

Post-COVID-19 vaccination

Only 1 case series exists of Adie’s tonic pupil-associated post-COVID-19 vaccination. Gönültas and colleagues described 2 patients, 1 patient was a 27-year-old woman and another was a 48-year-old man, 10 and 12 days after receiving the Pfizer vaccine [101]. 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 [101].

Horner syndrome

One report exists of a transient isolated Horner syndrome (HS) in a 65-year-old woman 3 days after being infected with COVID-19 [102]. 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 [102]. HS has not been reported yet in association with COVID-19 vaccination.

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

Although 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 [9,10,82,103,104].

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 such as the brain. Direct viral infection could explain some of the autoimmune disorders occurring in patients post-COVID-19 infection such as ON, cranial neuropathies, and Adie’s tonic pupils [8,55,105,106]. Retrograde transport of the virus particles to the central nervous system is thought to underlie some of these disorders and is supported by a postmortem case series that found that SARS-CoV-2 viral proteins in the cranial nerves of (53%) of the investigated patients [107]. Moreover, viral particles are thought to travel from the lungs to the autonomic center in the brain stem causing disorders such as HS [102]. Moreover, in cases such as GCA, the virus is thought to have an affinity to the vascular endothelium causing direct damage [31,108]. The SARS-CoV-2 virus can cause a disruption the blood–brain barrier by proinflammatory cytokines and result in increased permeability of the blood–brain barrier, which gives access for antibodies such as MOG antibodies to the central nervous system [109].

Reports also have suggested that COVID-19-induced hypoxemia and hypercoagulability can increase the risk of circulatory insufficiency and NA-AION [110,111]. Moreover, hypercoagulability and hyperviscosity can lead to venous congestion and IIH or CVST [49,54].

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 ON, the molecular mimicry between the virus and central nervous system (CNS) myelin, where they share the same amino acid sequence, leads to the formation of antibodies that attack myelin and cause demyelination [24].This theory also has been proposed for cranial neuropathies postvaccination where autoimmune inflammatory demyelinating peripheral neuropathy occurs [56,57,62]. A similar mechanism is well established in 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 [72,73]. Similarly in MG, the host immune system perceives the vaccine antigen as similar to host AChRs and attacks those receptors [87,88,90,92,94].

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 postvaccination [22,92,112].

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 [24,93,96]. Especially in those with symptoms occurring within a few days after receiving the vaccine [113].The presence of the human leukocyte antigen 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 [64]: NA-AION and IIH [40,51,52].

Summary

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 is 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 postvaccination 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-19 conditions can occur months after the COVID-19 infection.

Conflict of interest

None.

Source of support

None.