Case Report: Isolated, unilateral oculomotor palsy with anti-GQ1b antibody following COVID-19 vaccination

Neurological complications following vaccinations are extremely rare, but cannot be eliminated. Here, we report the first case of unilateral oculomotor nerve palsy (ONP) with anti-GQ1b antibody after receiving the Pfizer-BioNTech COVID-19 (BNT162b2) mRNA vaccine. A 65-year-old man developed diplopia and ptosis in the right eye 17 days after vaccination, without preceding infection. Neurological examination revealed mild blepharoptosis, limitation of adduction, and vertical gaze on the right side. Increased levels of anti-GQ1b ganglioside antibody in the serum and albuminocytologic dissociation in the cerebrospinal fluid were detected. Cranial magnetic resonance imaging showed swelling and enhancement of the right oculomotor nerve. The patient was diagnosed with right ONP accompanied with anti-GQ1b antibody, and intravenous immunoglobulin (IVIG) therapy for 5 days was administered. The limitation of adduction and vertical gaze improved, and ptosis markedly resolved after IVIG treatment. Given the temporal sequence of disease progression, laboratory findings, and a favorable response to IVIG, a causal relationship cannot be ruled out between the occurrence of ONP and COVID-19 immunization. Since immunomodulatory treatments significantly hasten the recovery and minimize the residual symptoms in anti-GQ1b antibody syndrome, clinicians should be aware of this clinical condition following COVID-19 vaccination.


Introduction
Oculomotor nerve palsy (ONP) is a neurological condition that manifests as diplopia, ptosis, and pupillary mydriasis.The various etiologies of ONP include cerebrovascular disease, cerebral aneurysm, diabetes, tumor, infection, collagen disease, hyperthyroidism, and Tolosa-Hunt syndrome 1 .In some cases, ONP can be caused by an aberrant immune response that develops directly against ganglioside GQ1b, a sialic acid-containing glycosphingolipid enriched in the paranodal region in the III (oculomotor), IV (trochlear), and VI (abducens) cranial nerves 2 .The para-infectious, immune-mediated ONP, along with ataxia and loss of tendon jerks, was originally described by Charles Miller Fisher as a variant of Guillain-Barré Syndrome (GBS) 3 .Compared to control subjects without neurological complications, the sensitivity and specificity of anti-GQ1b antibody in the patients with MFS are very close to 100% 2,4 .Since there are incomplete or atypical forms of Miller Fisher syndrome (MFS), an umbrella term, "anti-GQ1b antibody syndrome" has emerged to encompass these clinical conditions 5 .

Case description
A 65-year-old Asian male office worker began to notice persistent double vision without preceding upper respiratory or gastrointestinal infection.The diplopia worsened in the left gaze, and three days later, he developed right ptosis.He was vaccinated with a second dose of Pfizer-BioNTech COVID-19 (BNT162b2) mRNA vaccine 17 days before his presentation.His medical history included a seven-year history of diabetes, glaucoma, and benign paroxysmal positional vertigo.He did not have diabetic retinopathy or neuropathy in his right eye.His medication included one tablet per day of Canalia ® (teneligliptin and canagliflozin), a diabetic combination drug which the patient had been taking for one year and one drop per day of prostaglandin analogue eye drops for glaucoma (time taken for unknown).
The general medical condition of the patient on admission (day 22) was unremarkable.Neurological examination revealed mild blepharoptosis, limitation of adduction, and vertical gaze on the right side (Figure 1A) with convergence insufficiency.Pupils were slightly asymmetric (right: 3.5 mm, left: 3.0 mm) and the right pupil was slightly slowly reactive to light.The other cranial nerves were preserved normally.These findings were consistent with the diagnosis of right ONP.Gait was normal, with no evidence of muscle weakness, ataxia, or sensory disturbances.Deep-tendon reflexes are normally elicitable.

Amendments from Version 1
We added the information about the sensitivity and specificity of anti-GQ1b antibody in MFS patients in the 1st paragraph of introduction.
We added the data of oligoclonal bands and myelin basic protein in the diagnostic assessment section.
Since abnormal enhancement was occasionally observed in patients with diabetic oculomotor palsy, we deleted the corresponding sentence in the first paragraph of the discussion.In addition, we described the possible mechanism by which mRNA-based vaccine produce anti-GQ1b antibody and subsequent neurological deficits in the second paragraph of the discussion.
We added the patient's photographs of the last follow-up when he completely recovered on day 77 in Figure 1 C. cytoplasmic antibody (ANCA), cytoplasmic ANCA, and acetylcholine receptor antibodies were negative.Cerebrospinal fluid showed mild albuminocytologic dissociation with protein levels of 52 mg/dL (normal range: 10-40 mg/dL) and 2 mononuclear cells/mm 3 (normal range: 0-5 cells/mm 3 ).Oligoclonal bands were negative and myelin basic protein was less than 31.3pg/mL (normal range: < 102 pg/mL).Highresolution, constructive interference in steady-state magnetic resonance imaging (CISS-MRI) showed swelling with gadolinium enhancement in the right cavernous segment of the oculomotor nerve (Figure 2), but no signs of aneurysm, tumor, and inflammation in the cavernous sinus and orbital apex were noted.A nerve conduction study in the limbs was normal.

REVISED
Based on these clinical and laboratory findings, we diagnosed the patient with isolated, unilateral ONP associated with anti-GQ1b antibody and administered intravenous immunoglobulin (IVIG, 400 mg/kg) for consecutive 5 days.On the fourth day of IVIG administration (day 36), the limitation of the vertical gaze and ptosis mildly improved.There were no adverse events during or after the IVIG treatment.The patient was discharged on day 40 and was followed up at an outpatient clinic on day 52.The limitation of the adduction and vertical gaze markedly improved and ptosis completely resolved on day 52 (Figure 1B).The patient also noticed an improvement in his diplopia.He completely recovered on day 71 (Figure 1 C).The patient was afraid of receiving further vaccinations, including the COVID-19 vaccine.We explained to him that the incidence of GBS and MFS caused by vaccinations are extremely rare and the causal link between neurological complication and COVID-19 vaccinations is still unclear.It is undoubtedly true that benefits of vaccination outweigh the risks and the truth of the matter is that rare side effects shouldn't rule out vaccines.If he is going to be vaccinated in the future, we will carefully watch his condition and seek medical attention as soon as possible if he experiences any complications.

Discussion
We report the first case of isolated unilateral ONP with anti-GQ1b antibody following COVID-19 vaccination.Clinically, there were many similarities between our case and the previous four cases of unilateral ONP with anti-GQ1b antibody (Table 1) [17][18][19] .First, all cases, including ours, had ptosis without ataxia, and three cases showed normal deep tendon reflexes.Second, three patients demonstrated albuminocytologic dissociation in the CSF.Third, all of the cases showed a normal pattern in the nerve conduction studies.Finally, four patients were successfully treated with IVIG and/or steroids, with different recovery periods ranging from 22 days to 6 months [17][18][19] .From an etiopathological point of view, two cases of isolated ONP with anti-GQ1b antibody were preceded by acute upper respiratory tract infection or gastroenteritis within two weeks of onset 18,19 .On the other hand, there have been no case reports of vaccine-induced, isolated ONP with anti-GQ1b antibody.Similar to GBS, the majority of MFS and other anti-GQ1b antibody-associated disorders showed a good response to immunotherapy, such as IVIG and plasmapheresis.However, if ONP is the sole manifestation of anti-GQ1b antibody syndrome, it can be difficult to diagnose, leading to a substantial therapeutic delay.
A growing concern among recent coronavirus vaccines is vaccine-related side effects.The most commonly observed adverse events with COVID-19 vaccines are fatigue, headache, muscle and joint pain, fever, pain at the site of injection, and to a much lesser degree, severe allergic reactions including anaphylaxis.The occurrence of these side effects can be predicted based on what is already known about the clinical trials of other vaccines.While not all reported side effects are directly related to vaccine administration, life-threatening side effects such as thromboembolism and neurological complications, including GBS, have also been reported following COVID-19 vaccines.In the United States, as of July 13, 2021 there were 100 preliminary reports of GBS after receiving the Janssen COVID-19 vaccine and 1 death after 12.5 million vaccine doses administered.GBS usually develops 3-22 days after the administration of COVID-19 vaccines [10][11][12][13][14][15][16] .Although MFS following COVID-19 vaccination has not been reported so far, MFS can be observed from 5 to 21 days after immunization with influenza [7][8][9] , pneumovax 9 , and DPT vaccines 6 .Similarly, our case also presented with unilateral ONP with elevated anti-GQ1b antibody 17 days after Pfizer-BioNTech COVID-19 (BNT162b2) vaccination without any preceding infection.Based on the temporal sequence of disease progression, laboratory findings, and a favorable response to immunotherapy, the possibility that preceding COVID-19 vaccination may provoke unfavorable immune responses, leading to ONP in our patient, cannot be ruled out.BNT162b2 vaccine of messenger RNA enter the body and export spike proteins on the cell, which provoke the production of antibodies and T cell reactions 20 .These immunological alterations may produce neutralizing antibodies as well as anti-GQ1b antibody, thereby leading to unfavorable neurological complications.
It should be noted that ONP is the most common cranial neuropathy in patients with diabetes 21 .Diabetes not only causes ischemic neuropathy, but also induces chronic low-level  inflammation in peripheral nerves through the elevation of various inflammatory markers such as C-reactive protein, tumor necrosis factor, and interleukin-6 21 .Thus, one can imagine that the pre-existing diabetes in our case might impair oculomotor nerve function, thereby aggravating demyelinating oculomotor damage by the anti-GQ1b antibody.Indeed, diabetes has been reported as a risk factor for the exacerbation and poor outcomes of GBS [22][23][24] .

Conclusion
Unilateral, isolated ONP with anti-GQ1b antibody was observed following COVID-19 vaccination.Insufficient recognition of this treatable condition often leads to misdiagnosis, which delays the receipt of adequate immunomodulatory therapy.Physicians should consider this rare clinical entity, even when the classical triad of MFS is absent.While the benefits of COVID-19 vaccination substantially outweigh the rare, possible adverse events, healthcare professionals should carefully monitor the hazardous effects of all COVID-19 vaccines and continue to work closely to manage potential risks and to harness science and big data to drive feedback and recommendations.

Consent
Written informed consent was obtained from the patient for the publication of this case report and any associated images.
It would be interesting if the author could discuss the positivity of anti-GQ1b antibody in the general population patients (without clinical suspicion of GBS), including sensitivity and specificity of this antibody for diagnosing MFS.
In the discussion section, the author describes the possibility of diabetic cranial neuropathy.It would be interesting to know if the patient was tested for oligoclonal bands in the cerebrospinal fluid and serum anti-AQP-4 antibodies as part of unilateral optic neuritis differential diagnosis as his contrast-enhanced MRI demonstrates swelling and enhancement in the right oculomotor nerve.
Lastly, it would be interesting if the author could discuss or speculate on some of the pathophysiological mechanisms on how mRNA-based vaccines may be related to GBS or MFS.

Is the background of the case's history and progression described in sufficient detail? Yes
Are enough details provided of any physical examination and diagnostic tests, treatment given and outcomes?signs of NMOSD.Hence, we think it unlikely that anti-AQP-4 antibodies contribute to the manifestation of oculomotor nerve palsy in our case.Taking the above into consideration, we added the data of oligoclonal bands and myelin basic protein in the diagnostic assessment section as follows: "Oligoclonal bands were negative and myelin basic protein was less than 31.3pg/mL (normal range: < 102 pg/mL).".
Comment #3: Lastly, it would be interesting if the author could discuss or speculate on some of the pathophysiological mechanisms on how mRNA-based vaccines may be related to GBS or MFS.
Reply: Thank you very much for your comment.We add the possible mechanism by which mRNA-based vaccine produce anti-GQ1b antibody and subsequent neurological deficits in the second paragraph of the discussion as follows: "BNT162b2 vaccine of messenger RNA enter the body and export spike proteins on the cell, which provoke the production of antibodies and T cell reactions (19).These immunological alterations may produce neutralizing antibodies as well as anti-GQ1b antibody, thereby leading to unfavorable neurological complications." Competing Interests: None declared Reply: We humbly accept this reviewer's comment.We deleted the following sentence in the 1 st paragraph of the discussion: "In agreement with our case, cranial MRI demonstrated abnormal swelling, T2 hyperintensity, and gadolinium enhancement of the affected oculomotor nerve in classic forms of MFS, providing a useful tool for early diagnosis."

Competing Interests: None declared
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Figure 1 .
Figure 1.Eye movement of the patient demonstrating right oculomotor nerve palsy.(A) Mild blepharoptosis, limitation of adduction and vertical gaze on the right side on day 30.(B) The limitation of adduction and vertical gaze improved and ptosis completely resolved after IVIG treatment (day 52).(C) He completely recovered on day 71.

Figure 2 .
Figure 2. Contrast-enhanced CISS-MRI demonstrates the swelling and enhancement in the right oculomotor nerve (indicated by white dotted lines).

Table 1 . Summary of previous reports and present case.
URI, upper respiratory infection; CSF, cerebrospinal fluid; NCS, Nerve conduction study; MRI, magnetic resonance imaging; NA, Not available; IVIG, intravenous immunoglobulin.

Is the background of the case's history and progression described in sufficient detail? Yes Are enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Yes Is sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Yes Is the case presented with sufficient detail to be useful for other practitioners? Yes
Contrast-enhanced findings of the oculomotor nerve on MRI have been reported in diabetic oculomotor palsy and idiopathic oculomotor palsy (Zhao et al. 2021 1 ; Yang et al. 2020 2 ).This finding is not specific to MFS.

Reviewer Expertise: Neuropathy I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.
Comment #2: Elevated CSF protein is often observed in diabetes mellitus.Do you have follow-up data of CSF?If this condition is associated with GQ1b, there may be changes in CSF protein.Thank you very much for your comment.We are sorry but we did not perform followup CSF analysis.As you mentioned, albuminocytologic dissociation in CSF might have improved after the therapy.Comment #3: Contrast-enhanced findings of the oculomotor nerve on MRI have been reported in diabetic oculomotor palsy and idiopathic oculomotor palsy et al. 20211; Yang et al. 20202).This finding is not specific to MFS. Reply: