COVID-19 and Guillain-Barre Syndrome: a systematic review of case reports

Background: Guillain-Barre Syndrome (GBS) is a neurological autoimmune disease that can lead to respiratory failure and death. Whether COVID-19 patients are at high risk of GBS is unknown. Through a systematic review of case reports, we aimed to summarize the main features of patients with GBS and COVID-19. Methods: Without any restrictions, we searched MEDLINE, Embase, Global Health, Scopus, Web of Science and MedXriv (April 23 rd, 2020). Two reviewers screened and studied titles, abstracts and reports. We extracted information to characterize sociodemographic variables, clinical presentation, laboratory results, treatments and outcomes. Results: Eight reports (n=12 patients) of GBS and COVID-19 were identified; one was a Miller Fisher case. The age ranged between 23 and 77 years, and there were more men (9/102). GBS symptoms started between 5 and 24 days after those of COVID-19. The protein levels in cerebrospinal fluid samples ranged between 40 and 193 mg/dl. None of the cerebrospinal fluid samples tested positive for COVID-19. Six patients debuted with ascendant weakness and three with facial weakness. Five patients had favourable evolution, four remained with relevant symptoms or required critical care and one died; the Miller Fisher case had successful resolution. Conclusions: GBS is emerging as a disease that may appear in COVID-19 patients. Although limited, preliminary evidence appears to suggest that GBS occurs after COVID-19 onset. Practitioners and investigators should have GBS in mind as they look after COVID-19 patients and conduct research on novel aspects of COVID-19. Comparison with GBS patients in the context of another viral outbreak (Zika), revealed similarities and differences that deserves further scrutiny and epidemiological studies.


Introduction
COVID-19 is a disease for which practitioners and researchers are still learning signs/symptoms, risk factors, co-morbidities and outcomes. Although COVID-19 research is rapidly evolving, novel findings deserve in-depth scrutiny to formulate new hypothesis and make solid conclusions. This is the case of COVID-19 presenting along Guillain-Barre Syndrome (GBS), for which there are a few case reports [1][2][3][4][5][6] .
GBS is a neurological autoimmune disease that can deteriorate hastily, thus requiring high clinical suspicion, early identification and appropriate management. In the past, also in the context of a viral disease outbreak, it has been pinpointed that Zika virus may be a risk factor for GBS 7-10 . Whether  patients are also at high risk of GBS, is largely unknown. However, the extensive evidence between Zika virus and GBS 7-10 , makes it relevant to study and decipher if COVID-19 is also associated with GBS. Consequently, to understand the characteristics of patients with COVID-19 and GBS, and to identify potential patterns, we conducted a systematic review of case reports of COVID-19 and GBS.

Protocol and eligibility criteria
We conducted a systematic review (protocol registration: CRD42020182015) and adhered to the PRISMA guidelines (Extended data: Table S1 11 ). We searched case reports of COVID-19 and GBS, both as defined by case report. There were no exposures, interventions, comparison groups or specific outcomes, as we aimed to summarize and describe all case reports of COVID-19 and GBS. The patients could have been studied from any healthcare facility.

Information sources and search
We used six data sources (searched on April 23 rd , 2020): MEDLINE, Embase, Global Health, Scopus and Web of Science (the first three through OVID); we also searched MedRxiv. The search terms are available in Extended data: Table S2 11 . The search did not include any restrictions. Active surveillance of key neurological journals and academic news helped identify additional sources after the search was conducted.
Study selection and data collation Titles, abstracts and full-texts were studied by two reviewers independently (RMC-L and CA-F). Two authors (RMC-L and CA-F) agreed on a data extraction form and piloted it with one report. Extracted information included epidemiological background; disease onset and initial signs/symptoms; laboratory tests and case resolution. The extraction form was not modified during data collection. Data was collected by one reviewer (CA-F) and complemented by others (SR and JV-P).

Synthesis of results
The extracted information was synthesized qualitatively. Because of the limited number of reports and patients, we did not conduct a quantitative synthesis (e.g., meta-analysis).

Ethics
This is a systematic review of published case reports. The original reports, nor this work, provided any personal information of the patients. No human subjects were involved in this research. We did not seek authorization by an Ethics Committee.
Overall, the age ranged from 23 to 77 years, and there were more men (9/12) than women (Table 1).
In all but one patient, COVID-19 was diagnosed with molecular tests; one patient had the diagnosis made with serological tests ( Among GBS patients, 6 debuted with ascendant weakness and 3 with facial weakness (Table 1); in addition, 7 patients evolved to respiratory failure between 4 and 6 days after GBS onset (Table 1).
GBS patients received intravenous immune globulin at 400 mg/kg, and so did the Miller Fisher patient (Table 1). Regarding COVID-19 treatment, three patients received hydroxychloroquine or other medications, including lopinavir and azithromycin (Table 1).

Amendments from Version 1
As instructed by one reviewer, we removed all summary statistics (e.g., means/medias); only ranges and counts are being reported. We appreciate the relevant suggestion. Five patients had a favourable outcome with symptoms remission or mild persistent symptoms, four remained with relevant symptoms or required critical care, and one patient died ( Table 1). The Miller Fisher case had successful resolution (Table 1).

Discussion
Main findings GBS is emerging as a relevant disease that may appear in COVID-19 patients. Male predominance of GBS in COVID-19 patients seems to follow reports about more severe presentation versus its female counterparts. GBS in COVID-19 patients shows heterogeneous presentations both clinical (e.g., ascending or cranial nerve paralysis) and electrophysiological (e.g., axonal or demyelinating). Temporal correlation of GBS seems to occur after COVID-19 onset. Unlike individual case reports, this synthesis of several cases appears to suggest that GBS occurs after COVID-19 onset; nonetheless, this hypothesis deserves further verification with strong epidemiological evidence. Finally, it is too early to determine if the association between GBS and COVID-19 is related to direct viral neurotoxicity, autoimmunity, or both since no validated serological or polymerase chain reaction cerebrospinal fluid tests are commercially available.

GBS in the context of other viral disease
Although the viral characteristics differ greatly, it is still relevant to make initial comparisons with cases of GBS and Zika virus (Table 2), where there also appears to be a male predominance and the age profile seems similar 15,16 . In both contexts -COVID-19 and Zika -GBS variants with bilateral facial paralysis. On the other hand, cerebrospinal fluid protein levels seem higher in COVID-19 (Table 2).
The experience and management of Zika virus and GBS has provided relevant evidence. It taught us that GBS can be a potential complication during or (shortly) after a viral disease onset. As clinicians receive COVID-19 patients, a neurological examination should not be overlooked at admission and thereafter. Moreover, acknowledging that GBS can be a potential complication of COVID-19 should allow to secure resources (e.g., treatment) to successfully meet the needs of a GBS and COVID-19 patient.

Research needs
It is still premature to determine a predominance of any of the sociodemographic and clinical features herein summarized. Studies with larger samples and more rigorous design (e.g., retrospective cohorts) are needed to explore this potential association in greater detail to advance the evidence on sociodemographic profiles, clinical presentation and laboratory tests regarding GBS and COVID-19. This way, prognostic factors could be pinpointed so that people at greater risk can be timely managed.
Research comparing GBS associated with COVID-19 and GBS free of COVID-19 15 , will also be relevant. We encourage clinicians looking after patients with GBS and COVID-19 to report their experiences; furthermore, we invite them to build networks with colleagues and those whose reports were herein summarized, so that they can conduct more robust studies.

Limitations
Despite searching six databases, we found few case reports.
As it was the case with Zika virus 8,17 , more cases may appear later in the pandemic. As the COVID-19 pandemic progresses, clinicians should be aware that GBS and other variants are possible and relevant complications. Our review provides an important first step to better understand the presentation, clinical characteristics and outcomes of COVID-19 and GBS. Epidemiological studies can build on the evidence herein summarised to conduct more robust research.

Conclusions
GBS is emerging as a relevant neurological disease in COVID-19 patients. Its pathophysiology and both clinical and electrophysiological characteristics remain to be further studied. The GBS onset appears to occur after the COVID-19 presentation by several days. Practitioners and investigators should have GBS in mind as they look after COVID-19 patients and conduct further research on novel aspects of COVID-19.

Data availability
Underlying data All data underlying the results are available as part of the article and no additional source data are required. This project contains the following extended data: - Table S1: PRISMA checklist.

Extended data
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Characteristics GBS and Zika virus GBS and COVID-19
Temporal relationship Zika symptoms paralleled GBS in 48% of cases 16 .
In all but one case, COVID-19 symptoms preceded GBS by 5-24 days.
Possible mechanism Other periinfection mechanisms may be present.
Possible post-inflammatory syndrome.
GBS variants with bilateral facial paralysis.

CSF testing
In 10% of patients RT-PCR was positive in cerebrospinal fluid 16 .
All cases had a negative RT-PCR in cerebrospinal fluid.
Cerebrospinal fluid protein level ranged from 40mg/dl to 193mg/dl Prognosis Disability at 6 months: mainly facial 16 . Not reported.
Other body fluids Related to long periods of viriuria 16 . Not reported.