Guillain-Barré Syndrome and Unilateral Optic Neuritis Following Vaccination for COVID-19: A Case Report and Literature Review

ABSTRACT

A 71-year-old woman presented 2 weeks after vaccination with the first dose of Vaxzevria (AstraZeneca, Oxford) for COVID-19 with a left lower motor neuron facial nerve palsy, which progressed to bilateral involvement. This was accompanied by bilateral proximal leg weakness. She was diagnosed with the ‘facial diplegia with paraesthesia’ variant of Guillain-Barré syndrome. Seven weeks post vaccination she developed painless loss of vision in the right eye. The visual acuity in that eye was light perception only with a right relative afferent pupillary defect and right optic disc swelling. A diagnosis of optic neuritis was made and she received pulsed intravenous methylprednisolone for 3 days, followed by oral prednisolone. The optic neuritis recurred following initial cessation of steroids requiring an extended course of steroids. Despite this, she made a good visual recovery to 6/6 in the affected eye. We present this case and a review of the literature surrounding vaccination and the development of these conditions.

Introduction

Guillain-Barré syndrome (GBS) and optic neuritis (ON) are conditions that have been rarely reported following a number of vaccinations.^1,2 We present the unusual case of a patient who developed both conditions sequentially with a temporal association to vaccination for Coronavirus-2019 disease (COVID-19) with Vaxzevria (AstraZeneca, Oxford, United Kingdom).

Case report

A 71-year-old woman presented with lower back and abdominal pain followed by altered taste and sequential facial weakness 2 weeks following her first vaccination for COVID-19 with Vaxzevria. She described a ‘lack of awareness’ of her bowel and bladder, requiring effort to empty but with full control. Examination revealed bilateral lower motor neuron facial nerve palsies, with her being unable to close her eyes with effort. Over the next week she developed gait disturbance; examination revealed bilateral proximal leg weakness (Medical Research Council grade 4/5), absent knee and left ankle reflexes, and a normal sensory examination. The cardiovascular examination was normal.

One month prior to vaccination she presented with fevers, malaise and fatigue and was diagnosed with COVID-19, confirmed by polymerase chain reaction (PCR). These symptoms resolved aside from exercise-limiting fatigue.

Her medical history included an episode of embolic transient monocular visual loss and sciatica. She was taking clopidogrel and atorvastatin.

Routine blood investigations – including full blood count, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), renal and liver function, protein electrophoresis, connective tissue disease screen (including ANA and ANCA), and angiotensin-converting enzyme (ACE) – were normal, aside from a mild lymphopaenia. Anti-ganglioside antibodies were negative, as were Campylobacter, Borrelia, cytomegalovirus, hepatitis E, human immunodeficiency virus and syphilis serologies.

Initial imaging was undertaken by the acute medical team who were concerned about the possibility of a neurovascular insult. Initial brain computed tomography (CT) revealed mild small vessel disease only. Magnetic resonance imaging (MRI) of the brain excluded an acute infarct. Carotid artery duplex showed intimal thickening only.

A lumbar puncture demonstrated a raised cerebrospinal fluid (CSF) protein level of 0.96 g/L (normal < 0.5 g/L), with an acellular CSF. A CSF viral PCR for herpes viruses was negative. There were no oligoclonal bands in the CSF and no microbiological growth.

Nerve conduction studies showed features in keeping with acute demyelination: absent or low amplitude sensory action potentials in lower and upper limbs; prolonged median, tibial and peroneal distal motor latencies; and temporal dispersion of the right extensor digitorum brevis compound muscle action potential.

A diagnosis of the ‘facial diplegia with paraesthesia’ variant of GBS was made. The patient was managed conservatively with neuro-physiotherapy and gabapentin for analgesia, and discharged after 3 weeks. While the facial diplegia and back pain improved, she experienced paraesthesia in her hands and feet for the following weeks. All symptoms started to improve within 6 weeks of discharge.

Two weeks post-discharge (7 weeks post-vaccination) she represented with painless loss of vision in her right eye, that had occurred overnight. Examination revealed best corrected visual acuity (BCVA) of light perception only in the right eye and 6/9 in the left eye with a right relative afferent pupillary defect (RAPD). The right optic disc was swollen, with retinal nerve fibre layer (RNFL) thickening on optical coherence tomography (OCT). A diagnosis of right ON was made. She was treated with pulsed intravenous methylprednisolone (IVMP), 1 g daily for 3 days, and was admitted for further investigation.

Repeat MRI of the brain and orbits revealed high signal in the right optic nerve, consistent with ON (Figure 1). Repeat CRP and ESR were normal, as were aquaporin 4, myelin oligodendrocyte glycoprotein (MOG) and paranodal antibodies.

Figure 1.

Coronal orbital T2-weighted short tau inversion recovery magnetic resonance imaging demonstrating abnormal high signal in the right optic nerve (arrow).

Her visual acuity improved over 3 days to 6/60 unaided, 6/24 with pinhole in her right eye. Her RAPD persisted but the disc swelling had improved. She was discharged on 40 mg oral prednisolone daily, tapered down by 10 mg weekly. Ten days following discharge her visual acuity was 6/9 corrected in the right eye, 6/7.5 with pinhole. Her RAPD and disc swelling had resolved.

She completed the steroid course over the next month. Four weeks following this she represented with recurrence of the right ON, with a reduction of the BCVA to 6/18, reduced colour vision (scoring 4/17 plates on Ishihara testing), and an RAPD. Oral prednisolone 40 mg per day was restarted with a slower taper regime.

At 2 month follow up, her BCVA had improved to 6/9 with normal colour vision (17/17 plates on Ishihara testing) and resolution of the RAPD. There was no disc oedema and the visual fields were full. The RNFL returned to normal thickness, though there was evidence of atrophy of the ganglion cell layer. She had mild facial weakness but a full range of facial expression with complete eye closure with minimal effort (House-Brackmann grade 2).³ At 8 months her BCVA was 6/6 corrected. She described epiphora whilst eating due to aberrant regeneration of the facial nerve, and was due to begin a trial of botulinum toxin injections.

Discussion

ON is an inflammatory condition affecting the optic nerve. Its causes include demyelinating diseases (e.g. multiple sclerosis [MS]), infectious diseases (such as viral infection, Borrelia and tuberculosis) or autoimmune inflammatory processes (such as sarcoidosis, MOG antibody disease, neuromyelitis optica spectrum disorder [NMOSD], chronic relapsing inflammatory optic neuropathy, systemic lupus erythematosus, polyarteritis nodosa, and granulomatosis with polyangiitis).⁴

GBS is an autoimmune-mediated disorder affecting peripheral nerves. It is usually triggered by infection but may rarely be triggered by vaccination. In addition to clinical findings, the diagnosis of GBS is supported by investigations such as lumbar puncture with CSF analysis, neurophysiology studies, and blood tests for antiganglioside antibodies including anti-GM1 and anti-GQ1b. GBS can be classified into demyelinating forms, where the immune response targets the myelin sheaths surrounding the peripheral nerves, and axonal forms, where the axons themselves are targeted.⁵

ON is an uncommon feature of GBS, seen in demyelinating, but not axonal forms.⁶ Central nervous system (CNS) and peripheral nervous system (PNS) myelin originate from distinct cells – oligodendrocytes in the CNS and Schwann cells in the PNS – which differ in chemical structure and antigenic epitopes.⁷ The optic nerve is considered a part of the CNS due to its embryological development and central myelination.

Demyelinating lesions are usually limited to either the CNS or PNS. The simultaneous occurrence of combined central and peripheral demyelination (CCPD) is rare.^8,9 The combination of ON and GBS is a subtype of CCPD, along with other conditions such as acute demyelinating encephalomyelitis (ADEM), MS and chronic inflammatory demyelinating polyneuropathy. CCPD can appear post-infection or post-immunisation, the latter being more likely to have a monophasic rather than a relapsing course.¹⁰

The pathophysiology underlying demyelination in CCPD is poorly understood. An autoimmune process directed against common epitopes present in both CNS and PNS is likely mediated by autoreactive T-cells and/or autoantibodies crossing the blood/brain- and blood/nerve-barriers.¹¹ One such epitope, the GQ1b ganglioside, is targeted by autoantibodies in the Miller Fisher variant of GBS. GQ1b is found in relatively high concentration in the third, fourth and sixth cranial nerves, as well as in the optic nerve.¹² ON has occasionally been reported in Miller Fisher syndrome.^13–15 Neurofascins, which are nodal and paranodal proteins expressed at the nodes of Ranvier have recently been proposed as antigenic targets in demyelinating disorders. Among these, neurofascin-155 is expressed in both Schwann cells and oligodendrocytes and respective antibodies were found to be associated with a CCPD phenotype in recent studies.^14,15

Cases of ON and GBS are rare. Biotti et al. reviewed cases of ON and GBS, excluding anti-GQ1b associated presentations, in the English literature before 2011. They identified just 13 cases. The cases comprised simultaneous or sequential presentations, with ON preceding GBS by up to 12 days or succeeding it up to 3 months later. Some cases were associated with infections such as Mycoplasma pneumoniae, measles, Epstein-Barr virus or cytomegalovirus. The authors also reported a case of bilateral ON occurring after the patient received treatment for GBS with methylprednisolone and intravenous immunoglobulin (IvIg). This patient received further steroids and IvIg, with good motor outcome but mild improvement in visual function.¹⁶ Similar post-infectious cases have been reported since,^17,18 including a young woman with complete flaccid quadriplegia and facial diplegia secondary to GBS, along with bilateral optic disc oedema (likely due to raised intracranial pressure) and unilateral optic neuritis. This patient received IvIg with an excellent functional and visual recovery.¹⁹

GBS has been reported following vaccination for COVID-19, although it is rare.^20,21 The United Kingdom’s Health Security Agency have reported 472 cases of GBS after 24.9 million doses with the AstraZeneca vaccine, and 69 cases from 24.1 million doses with the Pfizer/BioNTech vaccine. This is based on cases reported to the Medicines and Healthcare products Regulatory Agency, from the yellow card reporting scheme.^22,23 They have report that cases are higher than expected for the AstraZeneca vaccine, with the risk being approximately 5.6 extra cases of GBS per million doses. This risk is not shared by the Pfizer/BioNTech vaccine.²² The yellow card reporting scheme also specifically looks at “Bell’s palsy”, finding similar rates to the expected natural rate.²⁴

Of 51 million doses of vaccine administered in the United States reported on the American Vaccine Adverse Event Reporting System (VAERS), 32 cases of GBS have been reported.²⁵ It is important to note that this does not imply causation. The ‘bifacial weakness with paraesthesia of limbs’ variant of GBS has been reported in five patients following COVID-19 vaccination, including our patient.²⁶

Isolated cases of ON have been reported rarely following different vaccines, though causation remains controversial. Another VAERS report from 1990–2017 found 187 cases of ON, of which 118 were defined as ‘definite’ cases. The majority of these occurred within 2 weeks, although cases were reported up to 6–8 weeks following vaccination. The authors suggested that the unbalanced distribution of cases in the first 6 weeks following vaccine suggests an association, though the rates reported were as expected for the general population.²⁷ In a case-centred analysis, Baxter et al. identified 91 confirmed cases of non-MS-related ON among more than 20 million vaccine exposures, with no evidence of clustering around exposure-related time intervals. They suggested no increased risk of ON following immunisation.¹ The UK MHRA yellow card report does not make note of vaccine-related ON,²⁴ although this does not exclude it as a possible complication. Garcia-Estrada et al. reported the case of a 19-year-old woman who developed ON 3 weeks after the Johnson & Johnson Ad26.COV2.S vaccine. This case is perhaps the first reported case of optic neuritis post-COVID-19 vaccination, and, like our case, had a good visual response to corticosteroids.²⁸

Vaccine-induced immune thrombotic thrombocytopenia (VITT), an autoimmune condition whereby antibodies trigger thrombosis via platelet activation is well recognised following COVID-19 vaccination with Vaxzevria; occurring in one in 100,000 vaccines in those over 50 years, and one in 50,000 in those under 50. It appears to be more common after the first dose.²⁹ Cerebral venous thrombosis is an important manifestation of VITT, being both more common and more severe in patients with VITT. Consideration should be given to these conditions when forming a differential diagnosis, particularly due to features such as visual disturbance, papilloedema and cranial nerve palsies due to raised intracranial pressure. Prompt recognition and treatment are vital to avoid significant morbidity and mortality.³⁰

Other authors have reported an association of a wide range of vaccines with the development of ON, including influenza,³¹ combined diphtheria/tetanus/pertussis/inactivated polio,³² measles, mumps and rubella,³³ and others. ON can occur as an isolated event, or may be the presenting symptom of NMOSD, ADEM, MS, or as part of the course of other diseases.³⁴

The underlying mechanism of post-vaccination ON is not clearly understood, although it is likely to be immune-mediated. Molecular mimicry, the process by which proteins elicit immune cross-reactivity, is one possible mechanism. The immune response to a component of the vaccine may therefore lead to immune dysfunction and subsequent inflammatory neuritis.^35,36 Activation of inflammatory pathways via the NLRP3 inflammasome has also been reported by COVID-19 vaccinations.³⁷ An alternative mechanism is that vaccine constituents, such as aluminium, trigger a neuro-inflammatory response after crossing the blood-brain barrier.^38,39 Roszkiewicz and Shoenfeld, however, found that isolated ON was more common in vaccines not containing aluminium, whilst ON associated with other CNS demyelination (such as NMOSD or MS) was found more frequently following vaccination containing aluminium; they postulated that this may support the proposal of neurotoxicity from these components.³⁴ Of note, Mitkus et al. developed an up-to-date analysis on the role of aluminium, given public concern on aluminium in vaccines. They concluded that episodic exposure to vaccines containing aluminium was significantly less than safe levels of environmental exposure, as recommended by the Agency for Toxic Substances and Disease Registry.⁴⁰

Initial treatment of post-vaccination ON involves steroids, typically intravenous methylprednisolone followed by a slow oral steroid taper.² In the review by Biotti et al. of 13 GBS-associated ON cases, the authors observed that, although the motor symptoms of GBS dramatically improved, the ON recovery was variable.¹⁶ Only four out of 13 cases reported recovery of visual acuity to 20/25 (6/7.5) or better, although the follow-up intervals varied. Improved visual outcomes in steroid resistant GBS-associated-ON has been reported using other immunotherapies such as IvIg,⁴¹ plasma exchange¹⁸ and rituximab.⁴² Similar to our case, Jun and Fraunfelder report a case of post-vaccination ON who relapsed after corticosteroid weaning,³¹ which clinicians should be mindful of when weaning treatment.

When considering such rare cases, it is important to consider a broad differential diagnosis; considering the possibility, for example, of transverse myelitis causing weakness or paraesthesia in patients with ON, which may suggest a diagnosis of NMOSD. Brainstem stroke, myasthenia gravis, MS and other causes of acute ophthalmoparesis, ptosis, mydriasis and facial weakness may also mimic GBS-related disorders.⁴³ The possibility remains in our patient that, due to her recent infection with COVID-19, her condition could be due to primary infection as opposed to vaccination. However, as described in the case series above, the time frame post-vaccination suggests an association.¹⁶

Our patient requested advice as to whether she should seek a second dose of vaccine. This is an area of limited evidence and advice will vary patient-to-patient. It is likely to be influenced by local prevalence, as well as the nature of the patient’s complication. Our patient underwent a booster without further complication. Firm evidence in this area would be helpful to clinicians and their patients, and highlights the importance of ongoing reporting of cases.

Conclusion

We have reported the first case of CCPD two weeks following Vaxzevria vaccination. Immunologically induced neurological syndromes caused by Vaxzevria vaccination remain rare, with benefits of vaccination far outweighing risk. It is vital for clinicians to be mindful of these associations when reviewing patients with new neurological conditions. Continued reporting of such cases will allow more robust analysis for public health concerns, and clinicians should be encouraged to undertake this.

Funding Statement

The authors reported there is no funding associated with the work featured in this article.

Declaration of interest statement

No potential conflict of interest was reported by the authors

Consent

We thank the patient described above for their support in producing this case report. Written consent was obtained for production of this report.