Case Series of Guillain-Barré Syndrome After the ChAdOx1 nCoV-19 (Oxford–AstraZeneca) Vaccine

Abstract

Purpose of Review

Vaccination has been associated with Guillain-Barre syndrome (GBS). Amid a global vaccination campaign to stop the spread of COVID-19, fears of GBS can contribute to vaccine hesitancy. We describe 3 cases of GBS in Calgary, Canada, presenting within 2 weeks of receiving the ChAdOx1 nCoV-19 (COVISHIELD) Oxford–AstraZeneca vaccination and review the available literature.

Recent Findings

All 3 patients presented to the hospital in Calgary, Alberta, Canada, within a one-month time frame with GBS. Their clinical courses ranged from mild to severe impairment, all requiring immunomodulatory treatment.

Summary

There is currently little evidence to support a causal relationship between vaccination and GBS. Furthermore, there is limited evidence to support recurrent GBS in patients with GBS temporally associated with vaccination. Neurologists should approach discussions with patients regarding GBS after vaccination carefully so as not to misrepresent this relationship and to educate patients that the risk of COVID-19 infection outweighs the small individual risk of a vaccine-associated adverse event.

Amid a global vaccination campaign against SARS-CoV-2 to control the COVID-19 pandemic, vaccine safety is monitored through the reporting of potential adverse events following immunization (AEFI) to public health authorities. One such event is Guillain-Barre syndrome (GBS), a rare acute inflammatory disorder affecting the peripheral nervous system. Fears of GBS not only halted the 1976-1977 Swine Flu vaccination campaign but have created harmful long-term associations between vaccinations and GBS and public caution regarding disease recurrence after further vaccinations.^1,2 However, a causal relationship remains equivocal because temporal association or geographic clustering of events are to be expected if large populations are vaccinated.³ We report 3 cases of GBS who presented after ChAdOx1 nCoV-19 (COVISHIELD) Oxford–AstraZeneca vaccination within a 1-month time frame. We discuss the relationship between vaccinations and GBS, the role of subsequent vaccinations in this population, and the importance of continued surveillance of AEFI and education surrounding vaccinations.

Case 1

A 40-year-old man with a history of nocturnal second-degree A-V block, but otherwise healthy, presented to the emergency department with ascending paresthesias from his feet to fingertips 10 days after receiving dose 1 of the ChAdOx1 nCoV-19 vaccine. He was initially discharged home as neurologic examination was normal but returned the same day with progression to bilateral leg weakness and difficulty ambulating. He was hypertensive at 154/95 mm Hg and had symmetric 4/5 Medical Research Council (MRC) grade weakness in shoulder abduction, hip flexion, knee flexion, and ankle dorsiflexion. Reflexes were decreased diffusely and absent in the right arm and at the ankles. Pinprick sensation showed patchy loss to the bilateral shins.

Investigations, including an MRI of the brain to support an alternative diagnosis, were negative. His rapid COVID-19 nasopharyngeal PCR swab was negative. His lumbar puncture on day 5 of symptoms showed normal white blood cell (WBC) count and a protein level. Electromyography and nerve conduction studies on day 5 of symptoms showed absent F-waves in the right ulnar and peroneal nerve despite normal compound motor action potentials, as well as F-wave impersistence in the tibial nerve, consistent with early acute inflammatory demyelinating polyradiculopathy.

He was diagnosed with GBS with autonomic dysfunction and started on intravenous immunoglobulin (IVIg) with a dose of 2 g/kg divided over the first 5 days of admission. After starting treatment, his clinical picture continued to evolve. He had worsening autonomic dysfunction, consisting of urinary retention and new-onset refractory hypertension (systolic pressures 170–190 mm Hg). One episode of nonsustained ventricular tachycardia was also captured on bedside telemetry. He developed severe headache thought to be aseptic meningitis from IVIG that resolved spontaneously after IVIG was completed. On day 5 of admission, he was diffusely areflexic and had progressive weakness in his bilateral upper and lower extremities requiring 2-person assistance while using a 2-wheeled-walker to ambulate. He developed a lower motor neuron left-sided facial weakness.

His neurologic symptoms began to improve around day 7 of admission or 2 days post-IVIg. His urinary retention resolved, and his blood pressure stabilized with 3 antihypertensive agents. On day 15 of admission, he was able to walk independently with the assistance of a 2-wheeled walker. He was discharged home on day 20 of admission with ongoing outpatient neurorehabilitation.

Case 2

A 53-year-old woman with a history of migraines developed bilateral paresthesias in her feet 12 days after her first dose of the ChAdOx1 nCoV-19 vaccine. She awoke the next morning with ascending paresthesias to her knees and bilateral lower extremity weakness and presented to the emergency department. On initial examination, her slow vital capacity (SVC) was 86% of predicted and motor power was 4/5 on the MRC scale throughout with diffusely reduced deep tendon reflexes. Lumbar puncture was normal, including WBC and protein. Rapid CoVID-19 nasopharyngeal PCR swab was negative. All basic bloodwork was normal.

A preliminary diagnosis of GBS was made based on her clinical presentation; she was promptly admitted to a general medicine unit, and treatment with IVIg was initiated. Her respiratory and motor status deteriorated rapidly, and less than 12 hours after presentation, she was intubated for neuromuscular respiratory failure.

After intubation, she was unable to trigger the ventilator. Cranial nerve examination was normal, but she otherwise had flaccid quadriplegia, except for muscle twitches to fingers and toes. Reflexes were absent throughout.

MRI of the spine with gadolinium contrast showed mild enhancement of the ventral roots in the cauda equina. Electromyography and nerve conduction studies showed evidence of a demyelinating polyneuropathy with features of temporal dispersion, conduction block, and F-wave prolongation consistent with a diagnosis of GBS.

On day 2 of admission, she was started on therapeutic plasma exchange for a total of 5 cycles over 10 days. Despite apheresis, her neurologic status continued to decline, and she had no gross movements to her bilateral upper or lower extremities on day 4. On day 9 of admission, she developed facial diplegia, and by day 13 of admission, she could only communicate with her eyes using a communication board. Given her prolonged respiratory failure, she underwent a percutaneous tracheostomy. Her course in hospital was complicated by a Klebsiella pneumoniae complex urinary tract infection, tracheitis, and conjunctivitis. At the time of submission 4 weeks from onset, her neurologic status remains unchanged in the intensive care unit, and repeat EMG/nerve conduction study showed absent motor and sensory responses in the arms and legs but no denervation potentials on electromyography.

Case 3

A 59-year-old man with a history of hypertension presented to the urgent neurology clinic 5 weeks after receiving the ChAdOX1 nCoV-19 vaccine with sensory symptoms and binocular diplopia. Two weeks after his vaccination, he developed symmetric numbness in the hands and lower extremities, up to his midthigh. Because of his symptoms, he required assistance with bathing and would use a wheelchair when outside of the house. One week later, he developed binocular horizontal diplopia, worse with right gaze. He presented to the emergency department and was referred for outpatient urgent neurology assessment. He was seen 4 days later in out-patient neurology clinic.

Neurologic examination at that time showed persistent sinus tachycardia, right cranial nerve VI palsy, and predominantly large fiber sensory loss in the hands and lower extremities. He was diffusely areflexic. He was subsequently admitted to the neurology inpatient service for further monitoring, investigations, and treatment. Lumbar puncture showed normal WBC with elevated protein level of 1.46 g/L (normal 0.15–0.45 g/L), consistent with albuminocytologic dissociation. Electrophysiologic studies were consistent with demyelinating polyneuropathy. They showed mild prolongation of right median distal motor latency without median sensory peak latency prolongation, prolonged F-waves in 4 of 5 nerves studied, and decreased median sensory nerve action potential amplitudes with sural sparing. Testing for antiganglioside antibodies was negative.

Correlating his clinical history and investigations, including electrophysiologic studies, a diagnosis of variant GBS (distal paresthesias and cranial nerve VI palsy) was made. Investigations did not reveal an alternative cause for his symptoms. He was treated with 2 g/kg of IVIg over 5 days, which was well tolerated. He remained clinically stable and was discharged home. At the time of discharge, he was independent with mobility, although not back to his premorbid baseline. At the time of writing, his vision has improved, and his ambulation continues to slowly improve.

An AEFI report was completed and sent to the local health authority for all 3 cases.

Based on the clinical history, laboratory investigations, imaging, and electrophysiologic studies, alternative diagnoses involving the central or peripheral nervous system were considered unlikely. There were no symptoms or signs to suggest preceding systemic infection such as GI symptoms, chest infections, influenza-like illness, or fever. COVID-19 testing was negative and therefore thought to be unlikely as a possible trigger of GBS. The PCR test used had 100% analytic specificity in the validation study of the assay.⁴ Because there is no gold standard, the performance of this test is not entirely known, but in a large retrospective cohort study, the sensitivity of this assay was found to be 90.7%.⁵ Noninfectious triggers of GBS such as preceding surgery, autoimmune disease, or immunosuppression were not identified.

Discussion

GBS remains the most common cause of acute flaccid paralysis worldwide. The underlying pathophysiology remains unclear but is thought to be related to molecular mimicry of antigenic agents triggering immune phenomena attacking peripheral nerve myelin sheaths.^6,7 This mechanism is also thought to be the underlying pathophysiology in cases of GBS associated with vaccination.^2,8-10 However, despite the association of GBS with multiple vaccines, there is no clear evidence to suggest a causal relationship.^11,12 We describe 3 cases of GBS following the first dose of the ChAdOx1 nCoV-19 vaccine. These cases highlight the development of GBS in a temporal relation to ChAdOx1 nCoV-19 vaccine in the absence of previously described triggers of GBS.^13-15

Currently, there is no evidence to suggest a causal relationship between vaccination against SARS-CoV-2 and GBS. Case reports of GBS have been described after both adenovirus vectors and synthetic messenger RNA COVID-19 vaccines, including the ChAdOx1 nCoV-19 vaccine.^16-18 The incidence of GBS was equal in the placebo and vaccine arm of the Johnson & Johnson COVID-19 vaccine trial, supporting that this relationship was temporal and likely coincidental, rather than causal.¹⁹ Our patients with GBS were geographically clustered and temporally associated with receiving the ChAdOX1 nCoV-19 vaccine, but this is not unexpected in mass vaccination campaigns and does not imply causation.^3,20-22 In a large population-based study of GBS in North America and Europe, the crude incidence of GBS was 0.81–1.89 cases per 100,000 person-years.²³ At the time of writing, approximately 2 million Albertans have received their first dose of a COVID-19 vaccine, and therefore, we would expect 16–38 cases of GBS by chance alone. There are fewer than 5 reports of GBS in Alberta as an AEFI in the Alberta COVID-19 vaccination campaign.²⁴ Our case series illustrates 3 cases of GBS, temporally associated with CoVID-19 vaccination; however, based on the current available data, the incidence of GBS is not higher after initiation of the CoVID-19 vaccination campaign compared with previously reported rates. This supports the previous literature suggesting that these cases may be coincidental events.^20-22

Current guidelines outlined by the Centers for Disease Control (CDC) and Prevention and Health Canada suggest that in patients with a history of GBS that developed <6 weeks in a temporal relation to a vaccine, recurrent vaccination must be approached with caution.^25,26 However, there is little evidence to support these recommendations. In those with a history of GBS that developed in temporal relation to a vaccination, there have been case reports of GBS recurrence after receiving the same vaccination for tetanus and influenza.^27-29 One case report describes one patient who, despite developing GBS after an influenza vaccine, continued to receive the influenza vaccine for 15 consecutive years without recurrence.³⁰ In one study surveying the British patient organization, the Guillain-Barré Syndrome Support Group, 29 respondents received a vaccine <6 weeks before developing GBS. Two of these 29 patients had a recurrence of symptoms after a different vaccine was administered.³¹ In a large case control study of 550 patients with GBS in the Kaiser Permanente Northern California database, 18 patients were confirmed to have GBS <6 weeks after receiving the influenza vaccine. Of the 18 patients, 2 patients received subsequent influenza vaccination with no recurrence of GBS. In addition, in all patients previously diagnosed with GBS who subsequently received multiple vaccines of various types, there was no recurrent case of GBS that would be associated with the vaccine, after nearly 1000 subsequent vaccinations.³² A subsequent nested case-control study over 3 cities in Jiangsu, China, including 1 056 patients with GBS, concluded there was no significant association between GBS recurrence and vaccinations for a number of different vaccines.¹²

It remains unclear if patients such as those reported here should receive subsequent SARS-CoV-2 vaccinations and which vaccine should be given. Preliminary studies are emerging assessing the efficacy of combining different SARS-CoV-2 vaccines.^33,34 A shared decision must be made between the patient, health care provider, and local health authorities, taking into account the potential risks and benefits. After discussion, given the partial protection achieved from a single dose of ChAdOx1 nCoV-19, none of the patients in this case series have elected to obtain a second dose of any SARS-CoV-2 vaccines. However, this decision will need to be reconsidered in the future if booster doses to address variants of concern become routine, similar to influenza vaccination campaigns.

The SARS-CoV-2 pandemic continues to devastate the world. The development of successful and safe vaccines and mass immunization campaigns will assist in ending the pandemic. It is crucial to avoid misinterpretation of AEFI as causally associated with vaccines because doing so will threaten the success of immunization campaigns, the development of future vaccines, and harm public trust in vaccines. It is important to continue ongoing vaccine safety surveillance programs, relying on population models to establish background incidence of adverse health outcomes and comparing them to observed rates.³ These programs and further large scale epidemiologic studies will provide further insight. In the meantime, neurologists must continue to provide ongoing patient education that the individual risk of developing GBS postvaccination is very small compared with the benefits of COVID-19 vaccination.

Limitations of this case series include the inability to completely rule out an asymptomatic infectious trigger of GBS, and there is limited follow-up of the cases. Continued surveillance of COVID-19 vaccines and potential adverse events remain crucial to further understanding this relationship.

Conclusion

We report 3 cases of GBS after the first doses of ChAdOx1 nCoV-19 vaccination. The geographic proximity and temporal association of these cases with vaccination do not imply causality from SARS-CoV-2 vaccination. There are no causal associations between vaccinations and the development of GBS or in the recurrence of GBS in patients who initially developed GBS <6 weeks from a vaccination. Large, long-term epidemiologic studies will continue to monitor vaccine safety. We must continue to emphasize that the risk of SARS-CoV-2 infection is far greater than the theoretical risks of GBS associated with SARS-CoV-2 vaccination.

Appendix. Authors

Study Funding

The authors report no targeted funding.

Disclosure

The authors report no disclosures relevant to the manuscript. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp.

TAKE-HOME POINTS

• → Currently, there is little evidence to support a causal relationship between vaccination and GBS. Neurologists should educate patients that the risk of COVID-19 infection outweighs a small individual risk of a vaccine-associated adverse event.

• → Particularly amid a global vaccination campaign, temporal association and geographic proximity of GBS cases after ChAdOx1 nCoV-19 vaccination does not imply causation.

• → Large, long-term epidemiologic studies will continue to study vaccine safety, including the incidence of GBS after vaccination and the risk of GBS recurrence in patients who developed GBS in temporal association with their first dose of COVID-19 vaccine.