Guillain-Barré syndrome associated with SARS-CoV-2 infection: a scoping review

Rev Assoc Med Bras 2021;67(2):318-334


INTRODUCTION
In December 2019, an outbreak of SARS-CoV-2, the virus that causes COVID-19 was detected in Wuhan City, Hubei Province of China.COVID-19 primarily affects the respiratory tract and the lungs and the appearance of symptoms depends on the age and the patient's underlying medical illness as well as on the condition of the immune system 1,2 .

Search
The medical subject headings (MESH) terms were (COVID-19 OR severe acute respiratory syndrome coronavirus 2 OR SARS-CoV-2) AND (Guillain Barre Syndrome OR Guillain-Barré Syndrome OR Landry-Guillain-Barre Syndrome OR Acute Autoimmune Neuropathy).Eligible studies were also selected from the reference lists of the retrieved articles.The research included articles published until June 26 th .

Selection of sources of evidence
Three authors, KSM, LTAM, and WFS, independently screened the search results using the titles and abstracts.Duplicate studies were excluded.The same authors then went through the full text to determine whether the studies met the inclusion criteria.Discrepancies were resolved by others reviewers, APFC, ACAS, and AKG.The selection of the studies was summarized in a PRISMA flow diagram (Figure 1).

Data items and Synthesis of results
Various characteristics of the eligible studies were extracted, including the first authors' last names, year of publication, location of the study (country), study design, primary objective, level of evidence, number of patients, gender, mean age of patients, comorbidities, clinical manifestations, muscle strength assessment, patient outcome, chest imaging, laboratory tests, tests diagnosis, and treatment.Standardized data extraction forms were specifically created in Excel for this review, and the results were entered into a database.All data entries were double-checked.Subsequently, the qualitative synthesis was summarized.

Critical appraisal of individual sources of evidence
The quality of the included studies was assessed using the New JBI Levels of Evidence developed by the Joanna Briggs Institute Levels of Evidence and Grades of Recommendation Working Party of October 2013 7 .Then, a Checklist for Case Series 8 and a Checklist for case reports were used 9 .

Selection of sources of evidence
The database search identified 196 articles.Excluding duplicates, a total of thirty-eight articles; one hundred and fifty-eight were considered eligible.However, forty-seven were excluded because titles and abstracts were considered Rev Assoc Med Bras 2021;67 (2):318-334 irrelevant to the topic or published before 2019.Subsequently, one hundred and eleven full-text articles were identified and assessed for eligibility.However, eighty-two publications were excluded because the data was insufficient to be extracted or calculated.Thus, twenty-nine articles were analyzed.The PRISMA-ScR flowchart for selecting the available studies is shown in Figure 1.

Critical appraisal within sources of evidence
Twenty-six articles were case reports (level of evidence 4.d) and three case series (level of evidence 4.c).Therefore, it was observed that the studies included in this review have low levels of evidence, according to the New Levels of Evidence from JBI 7 .This can be explained due to the recent appearance of the disease.Despite this, all studies were well designed and well evaluated by the JBI Critical Appraisal Checklist for Case Series 8 and        Case Reports 9 , that is, they achieved a high score and, thusly, were included in the review.

Clinical manifestations
Main clinical manifestations were fever, coughing, dyspnea, sore throat, ageusia, anosmia, respiratory failure, and diarrhea, as shown in Figure 2. Toscano et al. 10 describing three patients [P1, P3, and P5] who received mechanical ventilation and two who were admitted to the Intensive Care Unit (ICU) [P3 and P5].The condition of P5 deteriorates during hospitalization, presentation of hypercapnia, paradoxical breathing, and acidosis, leading to admission to the ICU, where mechanical ventilation by tracheostomy and pneumonia by acinetobacter is allowed.
Alberti et al. 12 describing a patient with hemodynamic disorders with severe drug-resistant hypertension and arterial blood gases indicate severe hypoxia.
Assini et al. 13 described a patient who needs tracheostomy and assisted ventilation [P2].
Ottaviani et al. 14 described a patient who was treated for organ failure, in addition to deep venous thrombosis of the legs and overlapping bacterial infection (pneumonia ab ingestis).
Rana et al. 18 described a patient who developed persistent difficulty in urinating, or who ended up requiring a permanent catheter.
Su et al. 19 described a patient who had a sputum culture Stenotrophomonas maltophilia, an organism associated with pneumonia associated with mechanical ventilation.

DISCUSSION
Until now, little is known about the neurological manifestations from COVID-19 and its direct relationship with GBS.The first case where neurological characteristics were observed standing out from the COVID-19 clinical symptoms was recently described; main symptoms included acute weakness in the legs and severe fatigue, with rapid progression 10 .For this reason, there are concerns that this virus is a possible trigger for GBS.
Sedaghat & Karimi 1 , in one case report, described GBS for the first time in a patient infected with COVID-19.The patient reported acute progressive symmetric ascending quadriparesis.Two weeks before hospitalization, the patient suffered from cough, fever, and RT-PCR was reported positive for COVID-19 infection.The electrodiagnostic test showed that the patient had an Acute Motor-Sensory Axonal Neuropathy (AMSAN) variant of GBS.
In the study carried out by Toscano et al. 10 , five patients with GBS after the onset of Covid-19 were examined.The first symptoms were lower-limb weakness and paresthesia in four patients and facial diplegia, followed by ataxia and paresthesia in one patient.In summary, flaccid tetraparesis or tetraplegia evolved from 36 hours to 4 days in four patients; three received mechanical ventilation.The interval between the onset of symptoms of Covid-19 and the first symptoms of GBS ranged from 5 to 10 days.This interval is similar that seen with GBS that occurs during or after other infections.As in previous studies, the authors point out that a possible relationship between these two diseases is the fact that COVID-19 through stimulation of inflammatory cells produces various inflammatory cytokines, and as a result, creates immune-mediated processes.As the GBS is an immune-mediated disorder, molecular mimicry as a mechanism of autoimmune disorder plays a vital role in its creation.
Zhao et al. 16 reported a woman who presented with acute weakness in both legs and severe fatigue, progressing within one day.Neurological examination disclosed symmetric weakness and areflexia in both legs and feet.Three days after admission, her symptoms progressed.Oropharyngeal swabs were positive for SARS-CoV-2 with RT-PCR assay.Considering the temporal association, it was speculated that the SARS-CoV-2 infection might have been responsible for the development of GBS.
Virani et al. 17 , in their study, described a case where the patient with COVID-19 presented neurological symptoms, including numbness and weakness of the extremities; consequently, there was a decrease in tendon reflexes with rapid progression.The mechanism proposed for this association is an autoimmune reaction where antibodies to surface glycoproteins are developed in the offending pathogen that also corresponds to similar protein structures of peripheral nerve components (molecular mimicry), leading to neurologic involvement.
Camdessanche et al. 21, in their study, also reported on one patient without medical history who was admitted after he fell and hurt the left shoulder, leading to a tear of the rotator cuff.He had a fever and cough for two days.SARS-CoV-2 RT-PCR with nasopharyngeal swab was performed and proved to be positive.Eleven days after symptom onset, the patient complained of paresthesia in both feet and hands.In three days, he demonstrated severe flaccid tetraparesis.The patient complained of swallowing disturbance with a risk of suffocation as liquids took the wrong path.The patient was admitted to ICU and mechanically ventilated due to respiratory insufficiency.
Padroni et al. 11 described a case of GBS following a clinically resolved paucisymptomatic COVID-19.The patient complained of asthenia, hands, and feet paresthesia, and gait difficulties, progressing within one day.Symptoms of COVID-19 were resolved in a few days.Neurological examination disclosed moderate symmetric distal upper and lower limb weakness, loss of deep tendon reflexes, preserved light touch, and pinpricking sensation.
Assini et al. 13 described two cases of GBS and COVID-19.In one of them, the patient needed invasive ventilation in the ICU and had an acute onset of bilateral eyelid ptosis, dysphonia, and dysphalgia 20 days after admission.Furthermore, through neurological examination, he demonstrated a deficit in the protrusion of the tongue due to bilateral paralysis of the hypoglossal nerve and hyporeflexia of the upper and lower limbs, along with bilateral masseter weakness.
Putting together all of these findings, the causal association between GBS and COVID-19 remains speculative but very probable.Neurologists and other clinicians should be aware of the essential early recognition and treatment of the potential neuromuscular and autonomic worsening leading to cardio-respiratory failure in patients with GBS and mild or controlled pulmonary COVID-19.More in-depth research should be carried out about this association, so that there is an established protocol of suitable diagnosis and treatment, in order to avoid high degrees of debilitation caused by GBS.

Limitations
The main limitation of this review was the lack of studies with a larger number of patients.

CONCLUSION
In conclusion, through well-designed primary studies, it is evident that COVID-19 can trigger GBS, as patients had clinical manifestations of COVID-19 infection and neurological manifestations characterizing GBS.Although the small number of patients limited our estimates, we believe that the results listed here are important for a better diagnosis and treatment of patients with neurological symptoms concomitant with respiratory symptoms

Figure 1 .
Figure 1.Flow diagram of the search for eligible studies COVID-19 and Guillain-Barre Syndrome: CENTRAL.Cochrane Central Register of Controlled Trials.

Figure 1 .
Figure 1.Flow diagram of the search for eligible studies COVID-19 and Guillain-Barre Syndrome: CENTRAL.Cochrane Central Register of Controlled Trials.

Table 1 .
Description of the characteristics of included studies. Continue...