The neurological safety of covid-19 vaccines

Dear Editor

The editorial by Pottegard and Klungel [1] on the neurological safety of COVID-19 vaccines reports that in the study by Li et al [2] neither the ChAdOx1 nCoV-19 nor the BNT162b2 COVID-19 vaccine was associated with an increased risk of neurological adverse events. Pottegard and Klungel state, “We may never be able to tell exactly what caused an individual to develop a neurological condition, but covid-19 vaccination is a highly unlikely reason for most.” However, we advise caution in generalising the findings of that study beyond what was reported.

First, Li et al examined a restricted list of four neurological conditions: Bell’s palsy, encephalomyelitis, Guillain-Barré syndrome and transverse myelitis and their findings were not fully in accordance with the review by Patone et al [3] (also discussed in the editorial by Pottegard and Klungel). The study conclusions should not, therefore, be extrapolated to suggest that for people who present with neurological conditions shortly after receiving a COVID-19 vaccine, the vaccine is a highly unlikely reason for the development of the neurological condition.

Second, the UK dataset used by Li et al uses only data collected from primary care, and only data which had been mapped to the relevant Systematized Nomenclature of Medicine (SNOMED) codes. While the limitation of only using primary care data was acknowledged, it is likely that the use of only these SNOMED codes will have led to many adverse neurological reactions not being captured, especially where presentations do not fit an established or expected diagnostic pattern.

We suspect that there is significant under-investigation and under-reporting of atypical post-vaccine presentations. There is evidence of a growing cohort of patients for whom this has been their experience with many presenting with “long COVID”-like symptomatology post-vaccination, [4] which appears to be significantly under-acknowledged in the literature. The causality of long COVID occurring after SARS-CoV-2 infection does not seem to suffer the same dismissal via post hoc ergo propter hoc as the link to similar symptoms occurring post-vaccination. This is despite the spike protein being a commonality, and post-vaccine neurological complications being recognised for other vaccines.

We have recently published on a preprint server two cases of post-vaccine neurological adverse reactions (one after BNT162b and one after ChAdOx1 nCoV-19). [5] Symptoms included sudden onset dizziness, facial paraesthesia, limb weakness, brain fog, word-finding difficulties, severe fatigue, bradykinesia, “jelly legs”, appetite and taste changes, polydipsia, tinnitus, micrographia, headaches, tachycardia, thermodysregulation, numbness and early waking. In one case, symptoms developed one to two weeks after the second dose of vaccine; in the other case, symptoms developed within hours of the first vaccine dose. In both cases, symptoms were fluctuant. One patient was able to continue working (but reported significant impairment of day-to-day functioning); the other patient required two periods of several weeks off work, during which they were near bed-bound. Both patients were found to have vitamin B12 deficiency.

One patient’s symptoms resolved with vitamin B12 replacement and as such we believe this was a case of post-vaccination demyelination with inadequate vitamin B12 for repair. The causal link to the vaccine was supported by their third vaccination dose, which induced a similar reaction that was once again resolved with vitamin B12 replacement. The other patient has reported incomplete symptomatic improvement (including continued episodic relapsing), although replacement with intramuscular vitamin B12 three times weekly is ongoing. As such, we believe this case to be post-vaccine syndrome presenting with neurological dysfunction, exacerbated (rather than caused) by B12 deficiency.

A recent systematic review found 32 cases of central nervous system (CNS) demyelination in association with COVID-19 vaccination, with clinical presentation being heterogeneous. [6] Furthermore, a case series reported 21 cases of new-onset, or flares of, inflammatory/autoimmune neurological conditions following COVID-19 vaccination, including eight cases of CNS demyelination and four cases of inflammatory peripheral neuropathies. [7] Such studies highlight the limited scope Li et al’s study was conducted within, and why generalisations to neurological reactions in general should be avoided.

At a population level, the net benefits of vaccination against COVID-19 have been clearly established. If, however, individuals develop an adverse reaction post-vaccine it is important that they are thoroughly clinically assessed, and that presentations are recorded using the relevant SNOMED codes or equivalent. Much research still fails to capture patients like our two cases who do not fit clear post-vaccine diagnostic criteria and indeed would likely have been missed in studies such as Li et al. Proper SNOMED coding will allow future studies to capture post-vaccine reactions beyond the four conditions studied by Li et al and would also aid in better understanding causality. Whilst at a population level risk may be very low, this does not preclude causality at an individual level; as such, we recommend patients with vaccine reactions are properly investigated when presenting with neurological adverse events post-vaccination.  

Patient consent obtained.

References
01. Pottegard A and Klungel OH. The neurological safety of covid-19 vaccines. BMJ 2022;376:o522
02. Li X, Raventos B, Roel E et al. Association between covid-19 vaccination, SARS-CoV-2 infection, and risk of immune mediated neurological events: population based cohort and self-controlled case series analysis. BMJ 2022;376:e068373
03. Patone M, Handunnetthi L, Saatci D et al. Neurological complications after first dose of COVID-19 vaccines and SARS-CoV-2 infection. Nat Med 2021;27:2144-53 doi:10.1038/s41591-021-01556-7. pmid:34697502
04. Couzin-Frankel J, Vogel G. In rare cases, coronavirus vaccines may cause Long Covid–like symptoms. Science 2022;375(6579):364-366
05. Carroll HA, Millar EC and Deans KA. Vitamin B12 and D deficiency as cofactors of COVID-19 vaccine-induced chronic neurological adverse reactions: Two cases and a hypothesis. Research Square 2022. doi:10.21203/rs.3.rs-1425014/v1
06. Ismail II and Salama S. A systematic review of cases of CNS demyelination following COVID-19 vaccination. J Neuroimmunol 2022;362:577765
07. Kaulen LD, Doubrovinskaia S, Mooshage C et al. Neurological autoimmune diseases following vaccinations against SARS-CoV-2: a case series. Eur J Neurol 2022;29(2):555-563