key: cord-0885927-o8k733dx
authors: De Sanctis, Paolo; Doneddu, Pietro Emiliano; Viganò, Luca; Selmi, Carlo; Nobile‐Orazio, Eduardo
title: Guillain Barré Syndrome associated with SARS‐CoV‐2 infection. A Systematic Review
date: 2020-08-05
journal: Eur J Neurol
DOI: 10.1111/ene.14462
sha: 56fe042ac51d333a59c413e069ab4e25af9c320d
doc_id: 885927
cord_uid: o8k733dx

BACKGROUND: Guillain‐Barré syndrome (GBS) incidence can increase during outbreaks of infectious illnesses. A few cases of GBS associated with coronavirus disease 2019 (COVID‐19) infection have been reported. To identify specific clinical features of GBS associated with COVID‐19. METHODS: We searched Pubmed, EMBASE and Cochrane from November 1, 2019 to May 17, 2020 and included all papers with full text in English, Spanish, French, or Italian, reporting original data of patients with GBS and COVID‐19. Data were extracted according to a predefined protocol. RESULTS: A total of 18 patients reported in 14 papers were included in this review. All the patients were symptomatic for COVID‐19, with cough and fever as the most frequently reported symptoms. The interval between the onset of symptoms of COVID‐19 and the first symptoms of GBS ranged from ‐8 to 24 days (mean 9 days; median 10 days). Most of the patients had a typical GBS clinical form predominantly with a demyelinating electrophysiological subtype. Mechanical ventilation was necessary in 8 (44%) patients. Two (11%) patients died. CONCLUSIONS: Published cases of GBS associated with COVID‐19 report a sensorimotor, predominantly demyelinating GBS with a typical clinical presentation. Clinical features and disease course seem similar to those observed in GBS related to other etiologies. These results should be interpreted with caution since only 18 cases have been heterogeneously reported so far.

Guillain Barré Syndrome (GBS) is a rare inflammatory disease of the peripheral nervous system with increasing incidence with age. 1 GBS is presumed to be triggered by preceding infections with specific pathogens. 1, 2 The typical onset is characterized by weakness and sensory signs starting in the legs and progressing to arms and cranial muscles. Loss of deep tendon reflexes, dysautonomic symptoms and pain are also common. Despite a heterogenous clinical presentation, diagnosis is based on the patient history and neurological examination, supported by electrophysiological studies showing a motor or sensorimotor polyradiculoneuropathy and cerebrospinal fluid (CSF) examination showing increased protein level with normal cell count. 2, 3 The incidence of GBS can increase during outbreaks of infectious illnesses that trigger the disease. 2 As reported by Lu H. et al, 4 in Wuhan City, Hubei Province of China a new-type of coronavirus (SARS-CoV-2, severe acute respiratory syndrome coronavirus 2 or COVID-19, coronavirus disease 2019) was detected in December 2019. This new virus has the capacity of entering into the cell through the fusion with angiotensin-converting enzyme 2 (ACE2) receptor. 5 The most recognizable feature of COVID-19 is to cause severe respiratory complications, which largely depends on the overall state of wellbeing of the infected patient. Age, patient's underlying comorbidities and the condition of the immune system also play a major role in the severity of the disease. 6, 7 Many signs and symptoms are associated with the infection such as fever, dyspnea, cough, headache and diarrhea. 8 Neurological manifestations are also increasingly reported, and a few cases of GBS in SARS-CoV-2 infected patients have been described. This study aims to summarize these cases into a single review to characterize GBS associated with SARS-CoV-2 infection.

This review follows the guidelines set forth by the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA). 9 A comprehensive literature search of the databases PubMed, EMBASE, and Cochrane was designed and conducted by the authors. The keywords Accepted Article used for the search are shown in Table 1 , which shows the primary research strategy. Initial search results were screened by checking only the title and abstract, then full-text articles from the resultant list were evaluated for inclusion. The search was supplemented by reviewing the bibliographies of the included papers to identify relevant publications. The search was limited to articles published from the period November 1, 2019 to May 17, 2020. The quality of studies has been assessed using the GRADE system by all the authors, until reaching a total agreement. 10 This study is a review of published literature and therefore is exempt from Institutional Review Board (IRB) approval.

The following predetermined criteria were used to screen the results: (1) Original case reports or (2) case series of patients diagnosed with GBS who tested positive for SARS-CoV-2 infection (3) written in English, Spanish, French or Italian.

For each paper the following data were extracted: number of patients reported, demographic characteristics, acute antecedent illness, clinical features associated with GBS including timing from antecedent illness to GBS onset, timing from GBS onset to nadir, GBS clinical subtype, Medical Research Council (MRC) score when reported, presence of cranial nerve involvement, dysautonomic symptoms, ataxia, type of treatment, outcome, medical interventions. Results of the ancillary investigations performed for GBS diagnosis were also reported, including cerebrospinal fluid (CSF) exam, Magnetic Resonance Imaging (MRI), and antigangliosides antibodies. GBS diagnosis was confirmed using the Brighton Collaboration criteria, specifying level of diagnostic certainty. 3 If the Brighton Criteria were not reported, these were estimated based on available reported data.

Results of the electrodiagnostic studies were reviewed and, when normal control values used were also reported, we revised the electrophysiological GBS subtype using the Rajabally's criteria, 11 otherwise subtype reported by the authors was included. We chose to use the Rajabally's criteria since they were shown to be the most appropriate for an indicative electrophysiological subtype diagnosis using a single electrophysiological study. 11 Symptoms and signs of SARS-CoV-2 infection, diagnostic testing, and treatment were also reported.

This article is protected by copyright. All rights reserved Clinical characteristics were retrieved as the number of patients in whom the variable was present in the numerator, and the total number of reported cases in the denominator: n/N (%). Variables not cited were considered absent or not performed rather than missing data (e.g. symptoms or diagnostic tests.

A total of 18 patients reported in 14 papers [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] Table 2 shows quality of evidence for each article. 10 Table 3 summarizes the demographics and clinical characteristics of each case with a reported GBS associated with SARS-CoV-2. Table 4 shows the diagnostic ancillary tests, outcome and treatment. Fourteen cases were from Europe, 12, [16] [17] [18] [19] [20] [22] [23] [24] [25] one from the US, 13 one from China, 14 one from Iran, 15 and one from Morocco 21 . Ten patients were males while 8 were females. Mean age was 62 years (median 64.5; range 23-77 years). In 14 patients, diagnosis of SARS-CoV-2 was confirmed by nasopharyngeal swab alone, in 3 patients by nasopharyngeal swab plus serological test, and in one patient by serological test alone (Table 5 ). All patients had signs of interstitial pneumonia at lung imaging tests except three. Cough (14 patients) and fever (13 patients) were the most frequent observed symptoms of SARS-CoV-2 infection in these patients, followed by dyspnea, ageusia, hyposmia, and diarrhea (Table 5 ). Two or more symptoms were present in 15 patients. None of the patients was asymptomatic for SARS-CoV-2 infection. The interval between the onset of symptoms of COVID-19 and the first symptoms of GBS ranged from -8 to 24 days (mean 9 days; median 10 days). In five patients an overlap between symptoms of COVID-19 and symptoms of GBS was reported. All patients had a typical GBS clinical form, except two patients with bilateral facial palsy, two patients with a paraparetic form, and one with a pure motor GBS. Eleven patients had a cranial nerve involvement, most frequently a unilateral or bilateral facial palsy that was present in 6 (33%) patients, a figure not different to that observed in GBS related to other etiologies (p= 1.000). 26 Three patients were ataxic and one had

This article is protected by copyright. All rights reserved dysautonomic symptoms (urinary retention). The nadir of neurological symptoms was reached in a mean of 5 days (median 4 days; range 2-17 days). Eleven patients met the Brighton Collaboration criteria level 1, five patients level 2, and two patients level 3. Electrophysiological studies were performed in all the patients but three. Criteria used to classify cases into the different electrophysiological subtypes were reported in only 7 patients. In three cases, the normal control values used for nerve conduction studies were reported and the electrophysiological subtype was revised: in two patients we confirmed an acute inflammatory demyelinating polyneuropathy (AIDP) subtype as reported by the authors, while in another we defined an AIDP subtype (not specified by the authors). The most frequent electrophysiological subtype was AIDP (10 patients), followed AMSAN (4 patients), and acute motor axonal neuropathy (AMAN) found in one patient. CSF was examined in all the patients except four.

Increased protein level and albuminocytological dissociation with normal cell count were present in 11 (61%) patients. Antigangliosides antibodies were tested in 6 patients, resulting negative in all. In ten patients, head and/or spine MRI was performed, showing enhancement of caudal nerve roots in two patients and of facial nerve bilaterally in one. Only six patients were tested for other infections that have been associated with GBS or acute polyradiculopathy ( Table 5 ). All tested cases were negative for a recent or ongoing non-COVID-19 infection, except one patient who was diagnosed with Clostridium difficile colitis and resulted positive for Rhinovirus at nasopharyngeal swab. In the CSF, polymerase chain reaction (PCR) test for SARS-CoV-2 was tested in 9 patients, resulting negative in all. All the patients except two were treated with intravenous immunoglobulin (IVIg); two received a second course of IVIg and one also plasma exchange. Outcome was reported in all the patients except four. Mechanical ventilation was necessary in 8 (44%) patients (all of them, except one, with a documented interstitial pneumonia at lung imaging). In all the patients mechanical ventilation was started after GBS onset.

Compared to GBS related to other etiologies, frequency of mechanical ventilation was not significantly different (p= 0.1788). 27 Intensive care unit (ICU) admission was necessary in six patients. Two patients died. Death was reported to be caused by progressive respiratory insufficiency in both the two patients, although it was not specified whether this was due to GBS or COVID-19. Frequency of death was not significantly different from that observed in GBS related to other etiologies (p= 0.1045). 28 In 8 patients, an improvement after treatment for GBS was observed whereas in 4 patients a poor outcome or lack of improvement was reported. In 11

This article is protected by copyright. All rights reserved patients, treatment for COVID-19 was initiated. The duration of follow-up was reported only in 10 patients and ranged from 4 to 30 days (mean 23 days; median 30 days).

Our systematic review shows that published cases of SARS-CoV-2-related GBS generally report a sensorimotor, predominantly demyelinating GBS with a typical clinical presentation. Clinical features and disease course seem similar to those observed in GBS related to other etiologies.

COVID-19 has infected almost five million individuals worldwide and killed over 314,319 people so far at the writing of this paper. 29 Neurological symptoms associated with SARS-CoV-2 infection have been observed by Mao et al, 30 but none of the 214 patients reported in their series had GBS. Serial electrophysiology has been suggested as more accurate than a single study to establish the electrophysiological subtype of GBS. 11, 31 Only one of the patients included in this review underwent a second electrophysiological study. In three patients we were able to revise the electrophysiological results using Rajabally's criteria. 11 The time between onset of infectious illness and the first neurological symptoms, the lack of cells in the CSF, the negative PCR assay for SARS-CoV-2 in the CSF performed in half of the patients, and the reported improvement after IVIg suggest a post-infectious dysimmune underlying pathological mechanism rather than a direct effect of the virus. Dysregulation of the immune system due to COVID-19 has been reported. 32 Positivity of nasopharyngeal swab and the presence of interstitial pneumonia in most of the patients may suggest a 'parainfectious' time pattern of GBS. However, if we consider that the incubation period of SARS-CoV-2 is about one week 33 and may be as long as 24 days in some patients, 34 a post-infectious mechanism seems more likely. This could also explain the reason for GBS predating COVID-19 symptoms in one patient. 14 These results should however be interpreted with caution since the cases included in this systematic review are variable in diagnostic ascertainment and reporting of variables. Only few of the patients were tested for other infectious agents that are known to be associated with GBS. One patient resulted positive for Clostridium difficile and Rhinovirus, but these infectious agents are not known to be associated with GBS 1,2 and they are commonly encountered in hospitalized patients. A coincidental association between COVID-19 and GBS remains possible. An Italian multicenter case control study is currently ongoing to investigate this association. The mean time between the onset of the antecedent infective symptoms and the start of neurological symptoms, the age distribution of the patients, the greater male frequency, the time to nadir of neurological

This article is protected by copyright. All rights reserved symptoms are all in line with previous studies on GBS. 1,2 All the patients except two fulfilled the Brighton criteria level 1 or 2. Antigangliosides antibodies were negative in all the patients who were tested. These antibodies are typically associated with the axonal variant of GBS, 35 

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This article is protected by copyright. All rights reserved