In the first place, the number of published case reports(4–10) stands out, on presumed Guillain-Barré syndrome secondary to COVID-19 infection, including the Miller-Fisher syndrome variant(11); from case series(12–15); as well as letters to the director or to the editor(16–17), through which it is not possible to establish strong evidence of a causal relationship given the absence of any type of statistical analysis, even more so considering the high prevalence (cumulative incidence in June 2021 of more than 170,000,000 cases worldwide) of SARS-COV2 infection in the areas where these cases occurred (Fig. 2), thus not being able to rule out the hypothesis that it was actually a simple coincidence(18–19) of two relatively frequent pathologies.
In addition, it is important to be able to adequately differentiate, in the case of patients affected by severe pneumonia, between critically ill neuropathy and Guillain-Barré syndrome, given the possible semiological overlap(20), especially considering that not all reported cases shows differentiating signs such as the classic albumin-cytological dissociation(21) in cerebrospinal fluid, as well as in many cases the typical latency time period of approximately 3 weeks from the causal infection and the appearance of neurological symptoms did not exist. For this reason, various sources call it early Guillain-Barré syndrome(22), and it is necessary to take into account the very possible diagnostic confusion.
However, the systematic reviews carried out do show a strong association between both pathologies, in addition, the studies analyzed emphasize differences in the presentation of the disease with greater severity in Guillain-Barré syndrome associated with COVID-19(23), compared to those described associated with other causes. In addition, an Italian multicenter observational study was published(24) that showed an increase in the incidence of Guillain-Barré syndrome from the start of the pandemic in northern Italy, supporting the existence of a link with this pathogen. They also agreed on the aforementioned observation that it usually presents more seriously than in cases precipitated by other causes. However, the confidence intervals overlapped due to the small sample size, and this small increase from previous years could be due to a chance finding(25).
To add even more confusion, we have an paper published in December 2020(26), which shows the results of a cohort study that found no association at all between Guillain-Barré syndrome and COVID-19 infection. The authors also did not find significant differences in the cases diagnosed during the pandemic, in terms of the pattern of weakness, latency time, neurophysiological patterns or findings in cerebrospinal fluid, compared to the cases diagnosed in the previous 3 years. Moreover, they corroborate a decrease in the incidence during the pandemic, which they explain as a consequence of the confinement measures adopted by the authorities, which would reduce the transmission of pathogens that induce Guillain-Barré syndrome, such as respiratory viruses or Campylobacter jejuni.
Generally, when measured, COVID-19 antibodies could not be determined in cerebrospinal fluid, except in one case(27). The viral amino acid sequence has been compared with human autoantigens associated with immune-mediated polyneuropathies, showing that the peptides that comprise the immunoreactive epitopes of SARS-COV2 share the same sequence as heat shock proteins 90 and 60 that are associated with Guillain-Barré syndrome(28–30). However, anti-ganglioside antibodies have only been detected very infrequently in some cases of Guillain-Barré syndrome associated with COVID19(31).
Regarding vaccination, the information we currently have is even scarcer than in the previous case, and even, of lower quality, highlighting some isolated case report published(32), some letter to the editor(33), and a study conducted in India(34), in which 80% of the population of Kerala (India) had received the ChAdOx1-S/nCov-19 vaccine. A period of 4 weeks (from March to April 2021) was evaluated in this population, observing 7 cases of Guillain-Barré syndrome, the incidence was therefore 1.4 to 10 times higher than that expected for such a period in a population of this magnitude. Guillain-Barré syndrome was also more severe, and the patients had frequently facial diplegia, a phenotype normally associated with post-vaccination Guillain-Barré syndrome(35).
On July 12, 2021, the FDA (Food and Drug Administration) referred that the Ad26.COV2.S (Janssen/Johnson & Johnson) vaccine registered an "increased risk" of Guillain-Barré syndrome. 100 cases were identified after the administration of 12.5 million doses of the vaccine. When making a critical reading, it is necessary to consider that if 4,000,000,000 people are immunized during a year, it would be expected that 68,000 cases of Guillain-Barré syndrome would occur naturally within this period, regardless of vaccination. Of these Guillain-Barré syndrome cases, 13,076 would occur in the 10-week window after double-dose vaccination with injections 4 weeks apart(36), which is even more than a hundred times more cases than reported by the FDA.
Therefore, more weighty, serious, epidemiological studies that may or may not demonstrate a real association are lacking.