Table 2

Criteria for defining causality in vaccine-related adverse events adapted from WHO criteria55 and from Bradford Hill criteria72

WHO GACVS criteria	Bradford Hill equivalent	Considerations for assessing causality of COVID-19 vaccination in organic neurological adverse events	Considerations for assessing causality of SARS-CoV-2 vaccination in FND
Is there evidence in published peer-reviewed literature that this vaccine may cause such an event if administered correctly?	Consistency, strengthandexperimental evidence	Limited evidence exists for new products, such as SARS-CoV-2 vaccines. Isolated cases, such as CVST with thrombocytopaenia in phase III Ad26.COV2.S trial, might have been reported in the clinical trials. Currently, multiple case reports and some epidemiological studies link VITT with adenovirus vector vaccines. However, only isolated case reports are available for Bell’s palsy, GBS, transverse myelitis and seizures, with no evidence from epidemiological studies.	In some widely circulated videos of SARS-CoV-2 vaccine reactions, objective clinical features suggestive of FND have been identified.51 67 Case reports of probable FND precipitated by SARS-CoV-2 vaccines have been recently published.63
Is there a biological plausibility that this vaccine could cause such an event?	Biological plausibility	The immune response to SARS-CoV-2 vaccines is the most likely mechanism for neurological AE. For example, vaccines are a recognised risk factor for GBS. However, confirming exact mechanisms and identifying responsible components of the vaccine (if any) may take a long time even in well-defined AE such as VITT.	Physiological reactions (eg, vasovagal symptoms or influenza-like symptoms), as well as injection site pain, may trigger and/or evolve into functional symptoms.26
In this patient, did a specific test demonstrate the causal role of the vaccine?	Coherence	Antibodies to platelet factor 4 have been used to confirm the diagnosis of VITT. However, it is recognised that not all patients will uniformly test positive. For other neurological events, specific tests can demonstrate the diagnosis (such as nerve conduction studies in GBS) but will not be able to attribute it directly to the vaccine.	FND is identified by positive clinical features. FND does not implicate specific vaccine constituents; it is precipitated by the physical procedure of being vaccinated.
Did the event occur within a plausible time window after vaccine administration?	Temporality	Most immune-mediated events are expected to develop days to weeks after vaccination. For VITT, the timeline is 5–30 days, although patients may present later (as thrombosis may be initially asymptomatic). For other immune-mediated neurological conditions, such as GBS or transverse myelitis, the standard cut-off is 42 days, although additional sensitivity analyses are often run using longer time intervals (up to 3 months). Events developing <24 hours (except for seizures) would be unlikely to be attributed to the vaccination.20 73	FND precipitated by vaccination can potentially arise within minutes if precipitated by the vaccination procedure itself but could also develop over days if precipitated by physiological effects of vaccination, for example, vasovagal or influenza-like side effects.
Could the current event have occurred in this patient without vaccination (background rate)?	Specificity	VITT has not been described prior to the adenovirus vaccines, and so baseline rates of CVST with thrombocytopaenia are unknown. Epidemiological studies may use CVST only as baseline rate, but such approach is limited. Baseline rates for GBS, transverse myelitis and Bell’s palsy are routinely used in vaccine surveillance. Beyond spontaneous occurrence, one must consider explaining the event by risks factors and alternative aetiologies. For example, one’s risk of Bell’s palsy is increased in pregnancy, whereas GBS may be triggered by infective illness.	FND is common26 and in many cases would arise independently of vaccination although, as discussed above, it may be a precipitating factor in some cases. Sociological and pandemic factors may further predispose those with a risk of FND to develop the disorder from a precipitating stressor, such as vaccination.62
Have similar events been observed in previous vaccination campaigns?	Analogy	Examples of neurological events associated with vaccinations include: 1976 Swine influenza vaccination association with GBS.20 74 2001 intranasal influenza vaccine association with Bell’s palsy.21 2010 childhood-onset narcolepsy following Pandemrix vaccination.16	Functional symptoms have been described following HPV22 69 as well as the H1N1 vaccination23 24 campaigns.

AE, autoimmune Encephalitis; CVST, cerebral venous sinus thrombosis; FND, functional neurological disorder; GBS, Guillain-Barré syndrome; HPV, human papillomavirus vaccination; VITT, vaccine-induced thrombosis with thrombocytopaenia.