Provisional case definitions for COVID-19-associated neurological disease

In The Lancet Neurology, Mark Ellul and colleagues¹ propose case definitions for the association of COVID-19 with neurological diseases. We would like to discuss the practicality of their definitions and the potential causality behind the associations, through the example of Guillain-Barré syndrome. Guillain-Barré syndrome can be easily differentiated from neurovirulent neuropathies, such as West Nile virus-associated neuropathy, and there is surveillance on its incidence in several countries, which renders Guillain-Barré syndrome a good candidate for assessing the association between infection and neurological disease.

Neurological disease occurring in the 6-week interval after acute infection is considered evidence for autoimmune association. However, typical acute respiratory symptoms are not always indicators of acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection; atypical presymptomatic or asymptomatic presentations of SARS-CoV-2 infection can occur before the onset of Guillain-Barré syndrome. Should we adopt the WHO-confirmed COVID-19 case definition¹ as the definition of SARS-CoV-2 infection? Moreover, should we use the screening date of a positive SARS-CoV-2 result as the onset of acute SARS-CoV-2 infection in all patients with Guillain-Barré syndrome without typical COVID-19 symptoms?

A possible association differs from a probable association in the evidence of other commonly associated causes. Although Ellul and colleagues¹ discuss evidence from other viruses as the cause of Guillain-Barré syndrome, influenza was not listed in their proposed case definitions for COVID-19-associated neurological disease. There is robust evidence on influenza-like illnesses as triggers for Guillain-Barré syndrome, and vaccination against influenza might reduce the risk of influenza-associated Guillain-Barré syndrome.² Early data showed a co-infection with influenza virus in about 50% of hospitalised patients with COVID-19.³ Co-infection of SARS-CoV-2 also exists in influenza-like illness.⁴ Therefore, influenza should be included among the possible causes of Guillain-Barré syndrome. Moreover, evaluation of the safety of a SARS-CoV-2 vaccine will face the same questions on whether Guillain-Barré syndrome is related to the infection itself or to the vaccine. Thus, information on the exact infectious agent is crucial for defining the adverse events of SARS-CoV-2 vaccines.

A pathogenic mechanism to link COVID-19 and Guillain-Barré syndrome has not yet been described. However, a molecular mimicry mechanism, autoimmune response against aberrant modification of nervous tissue by infection, and para-infectious immune dysfunction are common explanations for their potential association. We suggest that all these mechanisms should be investigated in COVID-19-related Guillain-Barré syndrome. For example, molecular mimicry with heat shock proteins (HSPs) was reported as a potential pathogenic mechanism of Guillain-Barré syndrome after SARS-CoV-2 infection.⁵ HSPs might also promote a superantigen response, which contributes to the para-infectious response.

To establish association and potential causality, researchers should endeavor to collect data from as many cases with COVID-19 as possible from whom SARS-CoV-2 is presumed as the single or joint cause, on the basis of accurate and timely diagnosis of SARS-CoV-2 infection.