PMC:7445716 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/7445716","sourcedb":"PMC","sourceid":"7445716","source_url":"https://www.ncbi.nlm.nih.gov/pmc/7445716","text":"Guillain–Barré syndrome spectrum associated with COVID-19: an up-to-date systematic review of 73 cases\n\nAbstract\nSince coronavirus disease-2019 (COVID-19) outbreak in January 2020, several pieces of evidence suggested an association between the spectrum of Guillain–Barré syndrome (GBS) and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Most findings were reported in the form of case reports or case series, whereas a comprehensive overview is still lacking. We conducted a systematic review and searched for all published cases until July 20th 2020. We included 73 patients reported in 52 publications. A broad age range was affected (mean 55, min 11–max 94 years) with male predominance (68.5%). Most patients showed respiratory and/or systemic symptoms, and developed GBS manifestations after COVID-19. However, asymptomatic cases for COVID-19 were also described. The distributions of clinical variants and electrophysiological subtypes resemble those of classic GBS, with a higher prevalence of the classic sensorimotor form and the acute inflammatory demyelinating polyneuropathy, although rare variants like Miller Fisher syndrome were also reported. Cerebrospinal fluid (CSF) albuminocytological dissociation was present in around 71% cases, and CSF SARS-CoV-2 RNA was absent in all tested cases. More than 70% of patients showed a good prognosis, mostly after treatment with intravenous immunoglobulin. Patients with less favorable outcome were associated with a significantly older age in accordance with previous findings regarding both classic GBS and COVID-19. COVID-19-associated GBS seems to share most features of classic post-infectious GBS and possibly the same immune-mediated pathogenetic mechanisms. Nevertheless, more extensive epidemiological studies are needed to clarify these issues.\n\nIntroduction\nCoronavirus disease 2019 (COVID-19) pandemic has rapidly spread around the world from Jan-2020, with more than 14,000,000 cases confirmed so far [1]. Although primary affecting the respiratory system, central and peripheral neurological manifestations associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have been increasingly reported [2–4]. In detail, several pieces of evidence suggested an association between SARS-CoV-2 infection and the development of Guillain–Barré Syndrome (GBS) [5–56].\nGBS represents the most common cause of acute flaccid paralysis [57]. The classic form is an immune-mediated acute-onset demyelinating polyradiculoneuropathy (acute inflammatory demyelinating polyneuropathy—AIDP) typically presenting with ascending weakness, loss of deep tendon reflexes, and sensory deficits. Diagnosis of GBS relies on the results of clinical, electrophysiological, and cerebrospinal fluid (CSF) examinations (classically albuminocytological dissociation) [57–59]. The clinical spectrum of GBS encompasses a classic sensorimotor form, Miller Fisher syndrome (MFS), bilateral facial palsy with paraesthesia, pure motor, pure sensory, paraparetic, pharyngeal–cervical–brachial variants, polyneuritis cranialis (GBS–MFS overlap), and Bickerstaff brainstem encephalitis [57–60]. As regard electrophysiological features, three main subtypes are recognized: AIDP, acute motor axonal neuropathy (AMAN), and acute motor sensory axonal neuropathy (AMSAN) [57, 58, 61]. Peripheral nerve damage is thought to be provoked by an aberrant immune response to infections, in some cases driven by the production of autoreactive antibodies (anti-ganglioside antibodies) [57–59]. Potential triggering pathogens include both viruses [e.g., cytomegalovirus (CMV), Epstein–Barr virus (EBV), influenza virus, hepatitis E virus, and Zika virus] and bacteria (e.g., Campylobacter Jejuni, Mycoplasma Pneumoniae) [57, 58, 62]. However, a relationship with other events has been also described (e.g., vaccinations, surgery, administration of checkpoint inhibitors, and malignancy) [57, 58]. Given that a potential causal association with beta-coronaviruses [Middle East Respiratory Syndrome (MERS-CoV)] has already been speculated, the relationship between COVID-19 and GBS deserves undoubtedly further attention [63, 64].\nWith this background, our systematic review aimed to provide a comprehensive and updated overview of all case reports and series of COVID-19-related GBS to identify predominant clinical, laboratory, and neurophysiological patterns and to discuss the possible underlying pathophysiology.\n\nMethods\nWe performed a systematic review according to the SALSA (Search, Appraisal, Synthesis, and Analysis) analytic framework [65]. We screened in PubMed and Google Scholar databases for all case descriptions of GBS associated with COVID-19 that were published from January 1st 2020 up to July 20th 2020. Keywords (including all commonly used abbreviations of these terms) used in the search strategy were as follows: [“acute autoimmune neuropathy” OR “acute inflammatory demyelinating polyneuropathy” OR “acute inflammatory demyelinating polyradiculoneuropathy,” OR “acute inflammatory polyneuropathy” OR “Demyelinating Polyradiculoneuropathy” OR “Guillain–Barre Syndrome” OR “Guillain–Barre” OR ““Miller–Fisher” OR “Bickerstaff encephalitis” OR “AIDP” OR “AMAN” OR “AMSAN” OR polyneuritis cranialis] AND [“COVID-19” OR “Wuhan coronavirus” OR “novel coronavirus” OR “novel coronavirus 2019” OR “SARS” OR “SARS-CoV-2”]. Suitable references were also identified in the authors’ archives of scientific literature on GBS. We restricted our search to studies published in English, Spanish, or Italian. Publications that were not peer-reviewed were excluded from this study. PRISMA criteria were applied. For each case, we extracted data concerning demographic and clinical variables, results of diagnostic investigations, and outcome. If the GBS clinical variant [57] or the electrophysiological subtype [61] was not explicitly reported in the paper, we reconstructed it, when possible, from reported details. We also classified the diagnostic certainty of all cases according to the Brighton Criteria [66]. Searches were performed by SAR, AA, and MF. The selection of relevant articles was shared with all authors.\nFor statistical analysis, we used IBM SPSS Statistics version 21 (IBM, Armonk, NY, USA). Based on the distribution of values, continuous data were expressed as mean ±  standard deviation or as  median and interquartile range (IQR). Depending on the number of groups and data distribution, we applied the t test, the Mann–Whitney U test or the Kruskal–Wallis test (followed by Dunn–Bonferroni post hoc test). All reported p values were adjusted for multiple comparisons. We adopted the Chi-square test for categorical variables. Differences were considered statistically significant at p \u003c 0.05.\nFor the present study, no authorization to an Ethics Committee was asked, because the original reports, nor this work, provided any personal information of the patients.\n\nResults\nOur literature search identified 101 papers, including 37 case reports, 12 case series, 3 reviews with case reports, 42 reviews, 4 letters, 1 original article, 1 point of view, and 1 brief report. Four and one patients were excluded from the analysis because of a missing laboratory-proven SARS-CoV-2 infection or an ambiguous GBS diagnosis [disease course resembling chronic inflammatory demyelinating neuropathy (CIDP)], respectively. A total of 52 studies were included in the final analysis (total patients = 73) [5–56]. All data concerning the analyzed patients are reported in Table 1. For one case [20], most clinical and diagnostic details were not reported; therefore, many of our analyses were limited to 72 patients.\n\nEpidemiological distribution and demographic characteristics of the patients\nTo date, GBS cases (n = 73) were reported from all continents except Australia. In details, patients were originally from Italy (n = 20), Iran (n = 10), Spain (n = 9), USA (n = 8), United Kingdom (n = 5), France (n = 4), Switzerland (n = 4), Germany (n = 3), Austria (n = 1), Brazil (n = 1), Canada (n = 1), China (n = 1), India (n = 1), Morocco (n = 1), Saudi Arabia (n = 1), Sudan (n = 1), The Netherlands (n = 1), and Turkey (n = 1) (Table 1, Fig. 1). The mean age at onset was 55 ± 17 years (min 11–max 94), including four pediatric cases [21, 27, 35, 41]. A significative prevalence of men compared to women was noticed (50 vs. 23 cases: 68.5% vs. 31.5%) with no significant difference in age at onset between men and women (mean: 55 ± 18 vs. 56 ± 16 years, p = 0.643). Comorbidities were variably reported with no prevalence of a particular disease.\nFig. 1 Temporal and spatial distribution of reported cases with COVID-19-associated Guillain–Barré syndrome in literature from 1st January until 20th July 2020. The x-axis shows the number of described patients. The y-axis illustrates the countries of provenience of the cases. In each line, different colours represent the months of April, May, June, and July (* until 20th July) 2020, in which the cases were published. Abbreviations: UK, United Kingdom, USA, United States of America\n\nClinical picture, diagnosis, and therapy of COVID-19\nAll reported GBS cases (n = 72) except two were symptomatic for COVID-19 with various severity. Most common manifestations of COVID-19 included fever (73.6%, 53/72), cough (72.2%, 52/72), dyspnea and/or pneumonia (63.8%, 46/72), hypo-/ageusia (22.2%, 16/72), hypo-/anosmia (20.8%, 15/72), and diarrhea (18.1%, 13/72). One of the two asymptomatic subjects never developed fever, respiratory symptoms, or pneumonia [10], whereas the other patient showed an asymptomatic pneumonia at chest computed tomography (CT) [12]. In all but six patients with available data [22, 24, 36, 44, 45, 52], SARS-CoV-2 RT-PCR with naso- or oropharyngeal swab or fecal exam was positive at first or following tests. Nevertheless, these six patients tested positive at SARS-CoV-2 serology. In four patients, the laboratory exam for the diagnostic confirmation was not specified [20, 40]. Typical “ground glass” aspects at chest-CT or similar findings at CT, Magnetic Resonance Imaging (MRI) or X-ray compatible with COVID-19 interstitial pneumonia were reported in 40 cases. The detailed therapies for COVID-19 are described in Table 1.\n\nClinical features of GBS spectrum\nIn all (n = 72) but four patients [10, 37, 40, 56], GBS manifestations developed after those of COVID-19 [median (IQR): 14 (7–20), min 2–max 33 days]. Differently, COVID-19 symptoms began concurrent in one case [37], 1 day [40] and 8 days [55] after GBS onset in two other cases and never developed in another one [10] (Table 1). Common clinical manifestations at onset included sensory symptoms (72.2%, 52/72) alone or in combination with paraparesis or tetraparesis (65.2%, 47/72, respectively). Cranial nerve involvement (e.g., facial, oculomotor nerves) was less frequently described at onset (16.7%, 12/72). Moreover, all cases but one [26] showed lower limbs or generalized areflexia, whereas in 37.5% (27/72) of the cases, gait ataxia was reported at onset or during the disease course. Even if ascending weakness evolving into flaccid tetraparesis (76.4%, 55/72) and spreading/persistence of sensory symptoms (84.7%, 61/72) represented the most common clinical evolutions, 50.0% (36/72) and 23.6% (17/72) patients showed cranial nerve deficits and dysphagia, respectively, during disease course (Table 1). Moreover, 36.1% (26/72) of the patients developed respiratory symptoms, and some of them evolved to respiratory failure (Table 1). Autonomic disturbances were rarely reported (16.7%, 12/72). In cases with MFS/MFS-GBS overlap, areflexia, oculomotor disturbances, and ataxia were present in 100% (9/9), 66.7% (6/9) and 66.7% (6/9), respectively [8, 19, 23, 30, 32, 33, 43, 44]. The median of time to nadir was calculated in 40 patients with available data and resulted 4 days (IQR 3–9) (Table 1).\n\nResults of electrophysiological, CSF, biochemical, and neuroimaging investigations\nDetailed electroneurography results were reported in 84.9% (62/73) of the cases. Specifically, 77.4% (48/62) cases showed a pattern compatible with a demyelinating polyradiculoneuropathy. In contrast, axonal damage was prominent in 14.5% (9/62). In a minority of the patients (8.1%), a mixed pattern was reported (5/62). Regarding CSF analysis (full results were available in 59 out of 73 cases), the classical albuminocytological dissociation (cell count \u003c 5/µl with elevated CSF proteins) was detected in 71.2% of the cases (42/59) with a median CSF protein of 100.0 mg/dl (min: 49, max: 317 mg/dl). Mild pleocytosis (i.e., cell count ≥ 5/µl), with a maximum cell count of 13/µl, was evident in 5/59 cases (8.5%). Furthermore, CSF SARS-CoV-2 RNA was undetectable in all tested patients (n = 31) (Table 1).\nDetailed blood haematological and biochemical examinations showed variably leucocytosis (n = 4), leucopenia (n = 17), thrombocytosis (n = 3), thrombocytopenia (n = 5), and increased levels of C-reactive protein (CRP) (n = 22), erythrocyte sedimentation rate (n = 4), d-Dimer (n = 5), fibrinogen (n = 3), ferritin (n = 3), LDH (n = 7), IL-6 (n = 4), IL-1 (n = 3), IL-8 (n = 3), and TNF-α (n = 3) (Table 1).\nFurthermore, anti-GD1b and anti-GM1 antibodies were positive in one patient with MFS [23] and in one with classic sensorimotor GBS [13], respectively, whereas 33 cases tested negative (one in equivocal range) for anti-ganglioside antibodies.\nCranial and spinal MRI scans were performed in a minority of the patients (23/73, 31.5%). Five patients (three cases with AIDP [9, 12, 25], one case with MFS [30], and one case with bilateral facial palsy with paresthesia [52]) showed cranial nerve contrast enhancement in the context of correspondent cranial nerve palsies. Moreover, brainstem leptomeningeal enhancement was described in two cases with AIDP, both with clinical cranial nerve involvement [18, 46]. On the other hand, spinal nerve roots and leptomeningeal enhancement were reported in eight [9, 27, 31, 36, 37, 42, 52] and two cases [17, 46], respectively (Table 1).\n\nDistribution of clinical and electrophysiological variants and diagnosis of GBS\nFrom the clinical point of view, most examined patients presented with a classic sensorimotor variant (70.0%, 51/73), whereas Miller Fisher syndrome, GBS/MFS overlap variants (including polyneuritis cranialis), bilateral facial palsy with paresthesia, pure motor, and paraparetic were described in seven, two, five, four, and one patients, respectively. In three cases, no clinical variant could be established using the reported details (Table 1). In the examined population, 81.8% subjects fulfilled electrophysiological criteria for AIDP (45/55), 12.7% (7/55) for AMSAN, and 5.4% (3/55) for AMAN subtypes. Finally, a specific electrophysiological subtype was not attributable in 18 patients due to the lack of detailed information. The diagnosis of GBS was established based on clinical, CSF, and electrophysiological findings in 44/73 (60.3%) patients, clinical, and electrophysiological data in 18/73 (24.7%) cases, clinical, and CSF data in 8/73 (11.0%), and only clinical findings in 3/73 (4.1%) patients. Indeed, the highest level of diagnostic certainty (level one) was confirmed in 44/73 cases (60.3%). Level two and three were obtained in 24/73 cases (32.9%) and 5/73 (6.8%), respectively (Table 1).\n\nManagement of GBS and patient outcomes\nAll cases with available therapy data (n = 70) except ten [13, 15, 23, 25, 26, 33, 35–37, 41] were treated with intravenous immunoglobulin (IVIG) (Table 1). Conversely, plasma exchange and steroid therapy were performed in ten (four of them received also IVIG) and two cases, respectively. In two patients, no therapy was given. Mechanical or non-invasive ventilation was implemented in 21.4% (15/70) and 7.1% (5/70) patients due to worsening of GBS or COVID-19, respectively. At further observation (n = 68), 72.1% (49/68) patients demonstrated clinical improvement with partial or complete remission, 10.3% (7/68) cases showed no improvement, 11.8% (8/68) still required critical care treatment, and 5.8% (4/68) died (Table 1).\nTable 1 Summary of clinical findings, results of diagnostic investigations, and outcome in 73 GBS cases\nArticle Country Age Sex GBS clinical picture COVID-19 clinical picture Previous comorbidities GBS diagnosis Level of diagnostic certaintyb GBS variant\nDays between COVID-19 symptoms and GBS onset Onset Disease course Autonomic disturbances Respiratory symptoms/failure Time to Nadira\nAgosti et al. [5] Italy 68 M 5 days after LL weakness Bilateral facial palsy, progressive symmetric ascending flaccid tetraparesis, achilles tendon areflexia NA No NA Dry cough associated with fever, dysgeusia, and hyposmia Dyslipidemia, benign prostatic hypertrophy, hypertension, abdominal aortic aneurysm Clinical + CSF + electrophysiology 1 Pure motor\nAlberti et al. [6] Italy 71 M 4 days after (no resolution of pneumonia) LL paraesthesia Ascendant weakness, flaccid tetraparesis, hypoesthesia and paraesthesia in the 4 limbs, generalized areflexia, dyspnea None Yes (concurrent pneumonia) 4 days after symptoms onset (24 h after the admission) Fever (low grade), dyspnea, pneumonia Hypertension, treated abdominal aortic aneurysm, treated lung cancer Clinical + CSF + electrophysiology 1 Classic sensorimotor\nArnaud et al. [7] France 64 M 23 days after Fast progressive LL weakness Generalized areflexia, severe flaccid proximal paraparesis, decreased proprioceptive length-dependent sensitivity and LL pinprick and light touch hypoesthesia None No 4 days after symptoms onset Fever, cough, diarrhea, dyspnea, severe interstitial pneumonia DM type 2 Clinical + CSF + electrophysiology 1 Classic sensorimotor\nAssini et al. [8] Italy 55 M 20 days after Bilateral eyelid ptosis, dysphagia, dysphonia Masseter weakness, tongue protusion (bilateral hypoglossal nerve paralysis), UL and LL hyporeflexia without muscle weakness, soft palate elevation defect None Yes (concurrent pneumonia) NA Fever, anosmia, ageusia, cough, pneumonia NA Clinical + electrophysiology 2 Classic sensorimotor overlapping with Miller-Fisher\nAssini et al. [8] Italy 60 M 20 days after Distal tetraparesis with right foot drop, autonomic disturbances UL and LL distal weakness, right foot drop, generalized areflexia Gastroplegia, paralytic ileus, loss of blood pressure control Yes (concurrent pneumonia) NA Fever, severe interstitial pneumonia NA Clinical + electrophysiology 2 Pure motor\nBigaut et al. [9] France 43 M 21 days after UL and LL paraesthesia, distal LL weakness Extension to midthigh and tips of the finger with ataxia, right peripheral facial nerve palsy, generalized areflexia None No 2 days after symptoms onset Cough, asthenia, myalgia in legs, followed by acute anosmia and ageusia with diarrhea, mild interstitial pneumonia NA Clinical + CSF + electrophysiology 1 Classic sensorimotor\nBigaut et al. [9] France 70 F 10 days after Acute proximal tetraparesis, distal forelimb and perioral paraesthesia Respiratory weakness, loss of ambulation None Yes 3 days after symptoms onset Anosmia, ageusia, diarrhea, asthenia, myalgia, moderate interstitial pneumonia Obesity Clinical + CSF + electrophysiology 1 Classic sensorimotor\nBracaglia et al. [10] Italy 66 F Unknown (due to asymptomatic infection) Acute proximal and distal tetraparesis, lumbar pain and distal tingling sensation Loss of ambulation, difficulty in speeching and swallowing, generalized areflexia None No NA Asymptomatic None Clinical + electrophysiology 2 Classic sensorimotor\nCamdessanche et al. [11] France 64 M 11 days after UL and LL paraesthesia Ascendent weakness, flaccid tetraparesis, generalized areflexia, dysphagia None Yes 3 days after symptoms onset Fever (high grade), cough, pneumonia None Clinical + CSF + electrophysiology 1 Classic sensorimotor\nChan et al. [12] Canada 58 M 20 days after home isolation for suspected contact Bilateral facial weakness, dysarthria, feet paraesthesia, LL areflexia NA None No NA Asymptomatic, interstitial pneumonia None Clinical + CSF + electrophysiology 1 Bilateral facial palsy\nwith paraesthesia\nChan et al. [13] USA 68 M 18 days after Gait disturbance, hands and feet paraesthesia LL proximal weakness, absent vibratory and proprioceptive sense at the toes, UL hyporeflexia, LL areflexia, unsteady gait with inability to toe or heel walk, bilateral facial weakness, dysphagia, dysarthria, neck flexion weakness None No 8 days after the onset of symptoms Fever and upper respiratory symptoms NA Clinical + CSF 2 Classic sensorimotor\nChan et al. [13] USA 84 M 16 days after Hands and feet paraesthesia, progressive gait disturbance Bilateral facial weakness, progressive arm weakness, neuromuscular respiratory failure Yes (not specified autonomic dysfunction) Yes 25 days after the onset of symptoms Fever NA Clinical + CSF 2 Classic sensorimotor\nCoen et al. [14] Switzerland 70 M 6 days after Paraparesis, distal allodynia Generalized areflexia Difficulties in voiding and constipation No NA Dry cough, myalgia, fatigue None Clinical + CSF + 0electrophysiology 1 Classic sensorimotor\nEbrahimzadeh et al. [15] Iran 46 M 18 days after Pain and numbness in distal LL and UL extremities, ascending weakness in legs Mild peripheral right facial nerve palsy, generalized areflexia None No 7 days after symptoms onset Low-grade fever, sore thorat, dry cough and mild dyspnea, bilateral interstitial pneumonia (concurrent with neurological symptoms) None Clinical + CSF + electrophysiology 1 Classic sensorimotor\nEbrahimzadeh et al. [15] Iran 65 M 10 days after Progressive ascending LL and UL extremities weakness and paraesthesia Proximal and distal UL and LL weakness, UL hyporeflexia and LL areflexia None No 14 days after symptoms onset History of COVID-19 (symptoms not specified), fine crackles in both lungs (concurrent with neurological symptoms) Hypertension Clinical + electrophysiology 2 Classic sensorimotor\nEl Otmani et al. [16] Morocco 70 F 3 days after Weakness and paraesthesia in the 4 limbs Tetraparesis, hypotonia, generalized areflexia, bilateral positive Lasègue sign None No NA Dry cough, pneumonia Rheumatoid arthritis Clinical + CSF + electrophysiology 1 Classic sensorimotor\nEsteban Molina et al. [17] Spain 55 F 14 days after Paraesthesia and weakness in the 4 limbs Lumbar pain, dysphagia, tetraplegia, general areflexia, bilateral facial palsy, lingual and perioral paraesthesia None Yes 3 days after symptoms onset (48 h after the admission) Fever, dry cough and dyspnoea, pneumonia Dyslipidemia Clinical + CSF + electrophysiology 1 Classic sensorimotor\nFarzi et al. [18] Iran 41 M 10 days after Paraesthesia of the feet Tetraparesis, areflexia at the LL and hyporeflexia at the UL, stocking-and-glove hypesthesia and reduced sense of vibration and position None No 7 days after symptoms onset Cough, dyspnea and fever DM type II Clinical + electrophysiology 2 Classic sensorimotor\nFernández–Domínguez et al. [19] Spain 74 F 15 days after Gait ataxia and generalized areflexia NA NA No NA Respiratory symptoms (not further detailed) Hypertension and follicular lymphoma Clinical + CSF 2 Miller Fisher variant\nFinsterer et al. [20] India 20 M 5 days after NA NA NA NA NA NA NA Clinical + electrophysiology 2 NA\nFrank et al. [21] Brazil 15 M \u003e 5 days after Paraparesis, pain in the LL Rapidly progressive ascending tetraparesis, areflexia NA No NA Fever, intense sweating NA Clinical + electrophysiology 2 Classic sensorimotor\nGigli et al. [22] Italy 53 M NA Paraesthesia, gait ataxia NA NA NA NA Fever, diarrhea NA Clinical + CSF + electrophysiology 1 NA\nGutiérrez-Ortiz et al. [23] Spain 50 M 3 days after Vertical diplopia, perioral paraesthesia, gait ataxia Right internuclear ophthalmoparesis and right fascicular oculomotor palsy, ataxia, generalized areflexia None No NA Fever, cough, malaise, headache, low back pain, anosmia, ageusia Bronchial asthma Clinical + CSF 2 Miller Fisher variant\nGutiérrez-Ortiz et al. [23] Spain 39 M 3 days after Diplopia (bilateral abducens palsy) Generalized areflexia None No NA Diarrhea, low-grade fever None Clinical + CSF 2 Polyneuritis cranialis (GBS–Miller Fisher Interface)\nHelbok et al. [24] Austria 68 M 14 days after Hypoaesthesia and paraesthesia in the LL, proximal weakness, areflexia, stand ataxia Ascending weakness, flaccid tetraparesis, generalized areflexia NA Yes 2 days after symptoms onset (24 h after the admission) Fever, dry cough, myalgia, anosmia and ageusia. None Clinical + CSF + electrophysiology 1 Classic sensorimotor\nHutchins et al. [25] USA 21 M 16 days after Right-sided facial numbness and weakness Bilateral facial palsy, severe dysarthria, bilateral LL weakness , bilateral UL paraesthesia, areflexia NA No 3 days after symptoms onset Fever, cough, dyspnoea, diarrhea, nausea, headache Hypertension, prediabetes, and class I obesity Clinical + CSF + electrophysiology 1 Bilateral facial palsy with paraesthesia\nJuliao Caamaño et al. [26] Spain 61 M 10 days after Facial diplegia No progression None No 1 day after symptoms onset Fever and cough None Clinical + electrophysiology 3 Bilateral facial nerve palsy\nKhalifa et al. [27] Kingdom of Saudi Arabia 11 M 20 days after Gait ataxia, areflexia and paraesthesia in the LL Gradual motor improvement, persistent hyporeflexia NA No NA Acute upper respiratory tract infection, low-grade fever, dry cough. NA Clinical + CSF + electrophysiology 1 Classic sensorimotor\nKilinc et al. [28] The Netherlands 50 M 24 days after Facial diplegia, symmetrical proximal weakness, paraesthesia of distal extremities, gait ataxia, areflexia Progression of limb weakness and inability to walk NA No 11 days after symptoms onset Dry cough None Clinical + electrophysiology 2 Classic sensorimotor\nLampe et al. [29] Germany 65 M 2 days after Acute right UL and LL weakness causing recurrent falls Right UL paresis, slight paraparesis more pronounced on the right side, generalized hyporeflexia None No 3 days after symptoms onset Fever and dry cough None Clinical + CSF + electrophysiology 1 Pure motor\nLantos et al. [30] USA 36 M 4 days after Opthalmoparesisa and hypoesthesia below knee Progressive ophthalmoparesis (including initial left III cranial nerve and eventual bilateral VI cranial nerve palsies), ataxia, and hyporeflexia None No NA Fever, chills, and myalgia None Clinical 3 Miller Fisher variant\nLascano et al. [31] Switzerland 52 F 15 days after (no resolution of pneumonia) Back pain, diarrhea, rapidly progressive tetraparesis, distal paraesthesia Worsening of proximal weakness (tetraplegia), generalized areflexia, ataxia Constipation, abdominal pain Yes 4 days after symptoms onset Dry cough, dysgeusia, cacosmia None Clinical + CSF + electrophysiology 1 Classic sensorimotor\nLascano et al. [31] Switzerland 63 F 7 days after (no resolution of pneumonia) Limb weakness, pain on the left calf Moderate tetraparesis, LL and left UL areflexia, distal hypoesthesia and paraesthesia None No 5 days after symptoms onset Dry cough, shivering, breathing difficulties, chest pain, odynophagia DM type 2 Clinical + electrophysiology 2 Classic sensorimotor\nLascano et al. [31] Switzerland 61 F 22 days after LL weakness, dizziness, dysphagia Moderate tetraparesis, bilateral facial palsy, lower limb allodynia, severe hypopallesthesia, areflexia (except for bicipital tendon reflexes) None Yes 4 days after symptoms onset Productive cough, headaches, fever, myalgia, diarrhea, nausea, vomiting, weight loss, recurrent episodes of transient loss of consciousness None Clinical + CSF + electrophysiology 1 Classic sensorimotor\nManganotti et al. [32] Italy 50 F 16 days after Diplopia and facial paraesthesia Ataxia, diplopia in vertical and lateral gaze, left upper arm dysmetria, generalized areflexia, mild lower facial defects, and mild hypoesthesia in the left mandibular and maxillary branch None Yes (concurrent pneumonia) NA Fever, cough, ageusia, bilateral pneumonia None Clinical + CSF 2 Miller Fisher variant\nManganotti et al. [33] Italy 72 M 18 days after Tetraparesis UL \u003e LL, LL paraesthesia , generalized areflexia, facial weakness on the right side NA NA No NA Fever, dyspnea, hyposmia and ageusia NA Clinical + CSF + electrophysiology 1 Classic sensorimotor\nManganotti et al. [33] Italy 72 M 30 days after Tetraparesis LL \u003e UL, paraesthesia, global areflexia NA NA No NA Fever, cough, dyspnea, hyposmia and ageusia NA Clinical + electrophysiology 1 Classic sensorimotor\nManganotti et al. [33] Italy 49 F 14 days after Ophthalmoplegia, limb ataxia, generalized areflexia, diplopia, facial hypoesthesia, facial weakness NA NA No NA Fever, cough, dyspnea, hyposmia and ageusia NA Clinical + CSF + electrophysiology 1 Miller Fisher variant\nManganotti et al. [33] Italy 94 M 33 days after LL weakness, generalized hyporeflexia NA NA No NA Fever, cough, gastrointestinal symptoms NA Clinical + electrophysiology 2 Classic sensorimotor\nManganotti et al. [33] Italy 76 M 22 days after Quadriparesis UL \u003e LL, generalized areflexia, facial weakness, transient diplopia NA NA No NA Fever, cough, dysuria, hyposmia, ageusia NA Clinical + CSF + electrophysiology 1 Pure motor\nMarta-Enguita et al. [34] Spain 76 F 8 days after Back pain and progressive tetraparesis with distal-onset paraesthesia Progressive with dysphagia and cranial nerves involvement, generalized areflexia NA Yes 10 days after symptom onset Cough and fever without dyspnea None Clinical 3 NA\nMozhdehipanah et al. [35] Iran 38 M 16 days after Progressive LL paraesthesia, facial diplegia, lobal areflexia Mild LL weakness , bulbar symptoms developed Blood pressure instability, tachycardia No 8 days after symptoms onset Upper respiratory infection (no further details) NA Clinical + CSF + electrophysiology 1 Bilateral facial palsy with paraesthesia\nMozhdehipanah et al. [35] Iran 14 F NA Ascending quadriparesis, UL hyporeflexia, LL areflexia, distal hypoesthesia, ataxia NA NA No NA Upper respiratory infection (no further details) NA Clinical + CSF 2 Classic sensorimotor\nMozhdehipanah et al. [35] Iran 44 F 26 days after Weakness of LL Tetraparesis, generalized areflexia, symmetrical hypoesthesia NA Yes NA Dry cough, fever, myalgia, progressive dyspnea COPD Clinical + CSF + electrophysiology 1 Classic sensorimotor\nMozhdehipanah et al. [35] Iran 66 F 30 days after Progressive UL and LL weakness, generalized areflexia, symmetrical hypoesthesia NA No No NA Fever, dry cough, severe myalgia DM, hypertension, and rheumatoid arthritis Clinical + CSF + electrophysiology 1 Classic sensorimotor\nNaddaf et al. [36] USA 58 F 17 days after Progressive paraparesis, imbalance, severe lower thoracic pain without radiation Mild neck flexion weakness, mild/moderate distal UL  and proximal and distal LL  weakness, UL hyporeflexia, LL areflexia, moderately severe length-dependent sensory loss in the feet, ataxic gait None No NA Fever, dysgeusia without anosmia, bilateral interstitial pneumonia None Clinical + CSF + electrophysiology 1 Classic sensorimotor\nOguz-Akarsu et al. [37] Turkey 53 F Concurrent pneumonia Dysarthria, progressive LL weakness and numbness Ataxia, generalized areflexia None No NA Mild fever (37.5 °C), pneumonia None Clinical + electrophysiology 2 Classic sensorimotor\nOttaviani et al. [38] Italy 66 F 7 days after (concurrent pneumonia) Flaccid paraparesis, no sensory symptoms Progressively developed proximal weakness in all limbs, dysesthesia, and unilateral facial palsy, generalized areflexia NA Yes 13 days after symptoms onset Fever and cough, pneumonia NA Clinical + CSF + electrophysiology 1 Classic sensorimotor\nPadroni et al. [39] Italy 70 F 23 days after UL and LL paraesthesia, gait difficulties, asthenia Ascendant weakness, tetraparesis, generalized areflexia None Yes 6 days after symptoms onset Fever (38.5 °C), dry cough, pneumonia None Clinical + CSF + Electrophysiology 1 Classic sensorimotor\nPaterson et al. [40] UK 42 M 13 day after Distal limb numbness and weakness, dysphagia Tetraparesis, generalized areflexia, sensory loss NA Yes 16 days after symptom onset Cough, fever dyspnea, diarrhea, anosmia None Clinical + CSF + electrophysiology 1 Classic sensorimotor\nPaterson et al. [40] UK 60 M 1 day before Distal limb numbness and weakness Tetraparesis, generalized areflexia, sensory loss, dysautonomia, facial and bulbar weakness Yes Yes 5 days after symptom onset Headache, ageusia, anosmia NA Clinical + CSF + electrophysiology 1 Classic sensorimotor\nPaterson et al. [40] UK 38 M 21 day after Distal limb numbness, weakness, clumsiness Mild distal weakness, sensory ataxia None No NA Cough, diarrhea NA Clinical + CSF + electrophysiology 1 Classic sensorimotor\nPaybast et al. [41] Iran 38 M 21 days after Acute progressive ascending paraesthesia of distal LL Quadriparesthesia, bilateral facial droop with drooling of saliva and slurred speech, generalized areflexia, swallowing inability, bilaterally absent gag reflex Tachycardia and blood pressure instability No 3 days after symptoms onset Symptoms of upper respiratory tract infection Hypertension Clinical + CSF + electrophysiology 1 Classic sensorimotor\nPaybast et al. [41] Iran 14 F 21 days after Progressive ascending quadriparesthesia, mild LL weakness Mild proximal and distal LL weakness, hypoactive deep tendon reflexes in UL and absent in LL, decreased light touch, position, and vibration sensation in all distal limbs up to ankle and elbow joints, gait ataxia None No 2 days after symptoms onset Symptoms of upper respiratory tract infection None Clinical + CSF 2 Classic sensorimotor\nPfefferkorn et al. [42] Germany 51 M 14 days after UL and LL weakness, acral paraesthesia Tetraparesis, generalized areflexia, deterioration to an almost complete peripheral locked-in syndrome with tetraplegia, complete sensory loss at 4 limbs, bilateral facial and hypoglossal paresis None Yes 15 days after symptoms onset Fluctuating fever, flu-like symptoms with marked fatigue and dry cough, pneumonia NA Clinical + CSF + electrophysiology 1 Classic sensorimotor\nRana et al. [43] USA 54 M 14 days after LL paresthesias of LL Ascending tetraparesis, general areflexia, burning sensation diplopia, facial diplegia, mild ophthalmoparesis Resting tachycardia and urinary retention Yes NA Rhinorrhea, odynophagia, fever, chills, and night sweats Hypertension, hyperlipidemia, restless leg syndrome, and chronic back pain, concurrent C. Difficile infection Clinical + electrophysiology 2 Miller Fisher variant\nReyes-Bueno et al. [44] Spain 50 F 15 days after Root-type pain in all four limbs, dorsal and lumbar back pain LL Weakness, ataxia, diplopia, bilateral facial palsy, generalized areflexia Dry mouth, diarrhea and unstable blood pressure No 12 days after symptoms onset Diarrhea, odynophagia and cough NA Clinical + CSF + electrophysiology 1 Miller Fisher variant\nRiva et al. [45] Italy 60+ M 17 days after Progressive limb weakness and distal paresthesia at four limbs Ascending paraparesis with involvement of the cranial nerves (facial diplegia), generalized areflexia None No 10 days after symptoms onset Fever, headache, myalgia, anosmia and ageusia NA Clinical + electrophysiology 2 Classic sensorimotor\nSancho-Saldaña et al. [46] Spain 56 F 15 days after Unsteadiness and paraesthesia in both hands Lumbar pain and ascending weakness, global areflexia, bilateral facial nerve palsy, oropharyngeal weakness and severe proximal tetraparesis No Yes 3 days after symptoms onset Fever, dry cough and dyspnea, pneumonia NA Clinical + CSF + electrophysiology 1 Classic sensorimotor\nScheidl et al. [47] Germany 54 F 11 days after Proximal weakness of LL, numbness of 4 limbs Initial worsening of the paraparesis with rapid improvement upon initiation of the treatment, areflexia None No 12 days after symptoms onset Temporary ageusia, None Clinical + CSF + electrophysiology 1 Paraparetic variant\nSedaghat et al. [48] Iran 65 M 14 days after LL distal weakness Ascending weakness, tetraparesis, facial bilateral palsy, generalized areflexia, LL distal hypoesthesia and hypopallesthesia None No 4 days after symptoms onset Fever, cough and sometimes dyspnea, pneumonia DM type 2 Clinical + electrophysiology 2 Classic sensorimotor\nSidig et al. [49] Sudan 65 M 5 days after Numbness and weakness in both UL and LL Ascending weakness, bilateral facial paraesthesia and palsy, clumsiness of UL, tetraparesis, slight palatal muscle weakness, areflexia Urinary incontinence Yes NA Low-grade fever, sore throat, dry cough, headache and generalized fatigability DM and Hypertension Clinical + electrophysiology 2 Classic sensorimotor\nSu et al. [50] USA 72 M 6 days after Proximal UL and LL weakness Progression with worsening of the paresis, areflexia, hypoesthesia Hypotension alternating with hypertension and tachycardia Yes 8 days after symptoms onset Mild diarrhea, anorexia and chills without fever or respiratory symptoms Coronary artery disease, hypertension and alcohol abuse Clinical + CSF + electrophysiology 1 Classic sensorimotor\nTiet et al. [51] United Kingdom 49 M 21 days after Distal LL paraesthesia LL and UL weakness, facial diplegia, distal reduced sensation to pinprick and vibration sense, LL dysesthesia, generalized areflexia None No 4 days after symptoms onset Shortness of breath, headache and cough Sinusitis Clinical + CSF + electrophysiology 1 Classic sensorimotor\nToscano et al. [52] Italy 77 F 7 days after UL and LL paraesthesia Flaccid tetraplegia, areflexia, facial weakness, dysphagie, tongue weakness None Yes NA Fever, cough, ageusia, pneumonia Previous ischemic stroke, diverticulosis, arterial hypertension, atrial fibrillation Clinical + CSF + electrophysiology 1 Classic sensorimotor\nToscano et al. [52] Italy 23 M 10 days after Facial diplegia LL paraesthesia, generalized areflexia, sensory ataxia None No 2 days after symptoms onset Fever, pharyngitis NA Clinical + CSF + electrophysiology 1 Bilateral facial palsy with paraesthesia\nToscano et al. [52] Italy 55 M 10 days after Neck pain, Paresthesias in the 4 limbs, LL weakness Flaccid tetraparesis, areflexia, facial weakness None Yes NA Fever, cough, pneumonia NA Clinical + CSF + electrophysiology 1 Classic sensorimotor\nToscano et al. [52] Italy 76 M 5 days after Lumbar pain, LL weakness Flaccid tetraparesis, generalized areflexia, ataxia None No 4 days after symptoms onset Cough and hyposmia NA Clinical + CSF+\nElectrophysiology 1 Classic sensorimotor\nToscano et al. [52] Italy 61 M 7 days after LL weakness and paraesthesia Ascending weakness, tetraplegia, facial weakness, areflexia, dysphagia None Yes NA Cough, ageusia and anosmia, pneumonia NA Clinical + CSF+ electrophysiology 1 Classic sensorimotor\nVelayos Galán et al. [53] Spain 43 M 10 days after Distal weakness and numbness of the 4 limbs, gait ataxia Progression of the weakness with bilateral facial paresis and dysphagia, generalized areflexia NA No 2 days after admission Cough, pneumonia NA Clinical + electrophysiology 2 Classic sensorimotor\nVirani et al. [54] USA 54 M 8 days after LL weakness, numbness Ascending weakness, tetraparesis, areflexia Urinary retention Yes Shortly after presentation in the outpatient clinic (after 2 days of symptoms onset) Fever (102 F), dry cough, pneumonia Clostridium difficile colitis 2 days before GBS onset Clinical 3 Classic sensorimotor\nWebb et al. [55] United Kingdom 57 6 days after Ataxia, progressive limb weakness and foot dysaesthesia, Tetraparesis, generalized areflexia, hypoesthesia in the 4 limbs, hypopallesthesia in LL, dysphagia None Yes 3 days after symptoms onset Mild cough and headache, myalgia and malaise, slight fever, diarrhea, pneumonia Untreated hypertension and psoriasis Clinical + CSF + electrophysiology 1 Classic sensorimotor\nZhao et al. [56] China 61 F 8 days before LL weakness Ascending weakness, tetraparesis, areflexia, LL distal hypoesthesia None No 4 days after symptoms onset Fever (38·2 °C), dry cough pneumonia NA Clinical + CSF + electrophysiology 1 Classic sensorimotor\nArticle COVID-19 diagnosis Blood findings Auto-antibodies and screening for most common GBS causes CSF findings Electrophysiology: Neuropathy type and GBS electrophysiologic subtype MRI (brain and spinal) Management and therapy Outcome\nGBS COVID-19\nAgosti et al. [5] RT-PCR + chest CT Thrombocytopenia (101 × 109 /L, reference value: 125–300 × 109 /L), lymphocytopenia (0.48 × 109 /L, reference value: 1.1–3.2 × 109 /L) Negative ANA, anti-DNA, c-ANCA, p-ANCA, negative screening for Campylobacter jejuni, Mycoplasma pneumoniae, Salmonella enterica, CMV, HSV 1 and 2, VZV, influenza virus A and B, HIV, normal B12 and serum protein electrophoresis Increased total protein (98 mg/dl), cell count: 2/106 L Demyelinating\nAIDP NA IVIG 400 mg/kg/day (5 days) Antiviral drugs (not specifically mentioned) Improvement, discharged home after 30 days\nAlberti et al. [6] RT-PCR + chest CT NA NA Increased total protein (54 mg/dl), 9 cells/µl, negative SARS-CoV-2 PCR Demyelinating\nAIDP NA IVIG 400 mg/kg (5 days) + mechanical invasive ventilation Lopinavir/ritonavir, hydroxychloroquine 24 h after admission, death because of respiratory failure\nArnaud et al. [7] RT-PCR + chest CT NA Negative anti-ganglioside and antineural antibodies, negative Campylobacter Jejuni, HIV, syphilis, CMV, EBV serology Increased total protein (1.65 g/L), no pleyocitosis, negative oligoclonal bands, negative SARS-CoV-2 PCR, negative EBV and CMV RT-PCR Demyelinating\nAIDP NA IVIG 400 mg/kg (5 days) Hydroxychloroquin, cefotaxime, azithromycine Progressive improvement\nAssini et al. [8] RT-PCR Lymphocytopenia, increased LDH and inflammation markers; low serum albumin (2.9 mg/dL) NA Normal total protein level, increased IgG/albumin ratio (233), negative SARS-CoV-2 PCR, presence of oligoclonal bands (both in serum and CSF) Demyelinating with sural sparing\nAIDP Brain: no pathological findings IVIG 400 mg/kg (5 days) Hydroxychloroquine, arbidol, ritonavir and lopinavir + mechanical invasive ventilation 5 days after IVIG, improvement of swallowing, speech, tongue motility, eyelid ptosis and strength\nAssini et al. [8] RT-PCR + chest CT Lymphocytopenia, increased LDH and GGT, leucocytosis, low serum albumin (2.6 mg/dL) Negative anti-ganglioside antibodies Normal total protein level, increased IgG/albumin ratio (170), negative SARS-CoV-2 PCR, presence of oligoclonal bands (both in serum and CSF) Motor sensory axonal, muscular neurogenic changes\nAMSAN NA IVIG 400 mg/kg (5 days) Hydroxychloroquine, antiretroviral therapy, tocilizumab + tracheostomy and assisted ventilation 5 days after IVIG, improvement of vegetative symptoms, persistence of hyporeflexia and right foot drop\nBigaut et al. [9] RT-PCR + chest CT Normal blood count, negative CRP Negative anti-ganglioside antibodies, negative HIV, Lyme and syphilis serology Increased total protein (0.95 g/L), cell count: 1 × 106/L, negative SARS-CoV-2 PCR Demyelinating\nAIDP Spinal: Radiculitis and plexitis on both brachial and lumbar plexus; multiple cranial neuritis (in III, VI, VII, and VIII nerves) IVIG 400 mg/kg (5 days) + non-invasive ventilation NA Progressive improvement\nBigaut et al. [9] RT-PCR + chest CT Increased CRP Negative anti-ganglioside antibodies Increased total protein (1.6 g/L), cell count: 6 × 106/L, negative SARS-CoV-2 PCR Demyelinating\nAIDP NA IVIG 400 mg/kg (5 days) NA Slow progressive improvement\nBracaglia et al. [10] RT-PCR (normal chest CT) Elevated CPK (461 U/L, normal \u003c 145), CRP 5,65 mg/dL (normal \u003c 0.5), lymphocyto- penia (0·68 × 109/L, normal 1·10–4), mild increase of LDH (284 U/L, normal \u003c 248), GOT and GPT (549 and 547 U/L, normal \u003c 35), elevation of IL-6 (11 pg/mL, normal \u003c 5.9) Negative anti-ganglioside antibodies; negative microbiologic testing on CSF and serum for HSV1-2, EBV, VZV, CMV, HIV, Mycoplasma Pneumoniae and Borrelia. Increased total protein (245 mg/dL) and increased cell count: 13 cells/mm3, polymorphonucleate 61.5% Demyelinating\nAIDP NA IVIG 400 mg/kg (5 days) Hydroxychloroquine, ritonavir, darunavir Improvement of UL and LL weakness, development of facial diplegia\nCamdessanche et al. [11] RT-PCR + chest CT NA Negative anti-gangliosides antibodies; negative screening for Campylobacter jejuni, Mycoplasma pneumoniae, Salmonella enterica, CMV, EBV, HSV1-2, VZV, Influenza virus A \u0026 B, HIV, and hepatitis E Increased total protein (1.66 g/L), normal cell count Demyelinating\nAIDP NA IVIG 400 mg/kg (5 days) + mechanical invasive ventilation Oxygen therapy, paracetamol, low molecular weight heparin, lopinavir/ritonavir 400/100 mg twice a day for 10 days NA\nChan et al. [12] RT-PCR + chest CT Persistent thrombocytosis (maximum PC 688 ×109/L), elevated d-dimer (1.47 mg/L) NA Increased total protein (1.00 g/L), cell count: 4 × 106/L (normal), negative SARS-CoV-2 PCR Demyelinating\nAIDP Brain: bilateral intracranial facial nerve enhancement IVIG 400 mg/kg (5 days) Empiric azithromycin and ceftriaxone Slight improvement of facial weakness, unchanged paraesthesia\nChan et al. [13] RT-PCR NA Negative anti-gangliosides antibodies Increased total protein (226 mg/dL), leucocytes: 3 cells/mm3, glucose: 56 mg/dL, negative SARS-CoV-2 PCR NA Lumbosacral spine: no pathological findings 5 sessions of plasmapheresis NA Resolution of dysphagia, ambulation with minimal assistance 28 days after symptoms onset\nChan et al. [13] RT-PCR NA Elevated GM2 IgG/IgM antibodies Increased total protein (67 mg/dL), leucocytes: 1 cells/mm3, glucose 58 mg/dL, negative SARS-CoV-2 PCR NA NA Mechanical invasive ventilation + 5 sessions of plasmapheresis (without benefit on ventilation) + IVIG NA Persistence of quadriparesis with intermittent autonomic dysfunction, slowly weaned from the ventilator\nCoen et al. [14] RT-PCR + serology Normal (not specified) Negative anti-gangliosides antibodies; negative meningitis/encephalitis panel Albuminocytological dissociation, no intrathecal IgG synthesis, negative SARS-CoV-2 PCR Demyelinating with sural sparing\nAIDP Brain: NA\nSpinal: no pathological findings IVIG 400 mg/kg (5 days) NA Rapid improvement. From day 11 from hospitalisation\nRehabilitation\nEbrahimzadeh et al. [15] RT-PCR + chest CT Normal CRP (5 mg/L), normal serum protein immunoelectrophoresis Negative anti-GQ1b antibodies, negative screening for Campylobacter jejuni, HIV, EBV, CMV, influenza virus (type A and B), HCV, non-reactive VDRL Increased total protein (78 mg/dL), normal cell count (erythrocyte = 0/mm3, leukocyte = 4/mm3), normal glucose (70 mg/dL) Demyelinating\nAIDP Brain: no pathological findings\nSpinal: no pathological findings None Hydroxychloroquine for 5 days Improvement of muscle strength to near normal after 16 days\nEbrahimzadeh et al. [15] RT-PCR + chest CT Slightly elevated CRP (34 mg/L), normal serum protein immunoelectrophoresis Negative anti-GQ1b antibodies, negative screening for Campylobacter jejuni, HIV, EBV, CMV, influenza virus (type A and B), HCV, non-reactive VDRL NA Demyelinating\nAIDP NA IVIG NA Improvement of muscle strength in all extremities after 14 days\nEl Otmani et al. [16] RT-PCR + chest CT Lymphocytopenia (520/ml) NA Increased total protein (1 g/L), normal cell count, negative PCR assay for\nSARS-CoV-2 Motor sensory axonal\nAMSAN NA IVIG 400 mg/kg/day (5 days) Hydroxychloroquine 600 mg/day; azithromycin 500 mg at the first day, then 250 mg per day At week 1 from admission no significant neurological improvement\nEsteban Molina et al. [17] RT-PCR + chest X-ray Leucocyte 7400/mm3, lymphocyte 2400/mm3. Hb 14 g/dl. PC 408,000/mm3, d-Dimer 556 ng/ml. Ferritin 544 ng/ml, CRP 2.04 mg/dl, Fibrinogen 6.8 g/dl Negative bacteriological and viral tests Increased total protein (86 mg/dL), cell count: 3x106/L Demyelinating\nAIDP Brain: leptomeningeal enhancement in midbrain and cervical spine IVIG 400 mg/kg/day (5 days) Hydroxychloroquine, azithromycin, ceftriaxon Motor improvement but persistence of paraesthesia\nFarzi et al. [18] RT-PCR + chest CT Lymphopenia (WBC:5.9 × 109/L, neutrophils: 85%, lymphocyte:15%), elevated levels of CRP, ESR 69 mm/h NA NA Demyelinating\nAIDP NA IVIG (2 g/kg over 5 days) Lopinavir/ritonavir and hydroxychloroquine Improvement after 3 days, favorable outcome\nFernández–Domínguez et al. [19] RT-PCR NA Negative anti-GD1b antibodies, negative other anti-ganglioside antibodies Increased total protein (110 mg/dL), albuminocytological dissociation Demyelinating\nNA Brain: no pathological findings IVIG 20 g/day (5 days) Hydroxychloroquine, lopinavir/ritonavir NA\nFinsterer et al. [20] NA NA NA NA Axonal\nAMAN NA IVIG NA Recovery\nFrank et al. [21] RT-PCR, + serology (IgG and IgM) WBC and CRP normal Negative hepatitis B and C, HIV and VDRL tests Two CSF analysis 2 weeks apart, both showing normal cell count and CSF biochemistry, negative SARS-CoV-2 PCR, negative PCR for HSV1, HSV2, CMV, EBV, VZV; Zika virus; Dengue virus and Chikungunya virus Axonal\nAMAN Brain: no pathological findings\nSpinal: no pathological findings IVIG 400 mg/kg/day (5 days) Methylprednisolone, azithromycin, albendazole Some improvement, weakness persisted\nGigli et al. [22] Chest CT + serology (negative RT-PCR) NA Negative anti-ganglioside antibodies, negative PCR for influenza A and B viruses (nasal swab) Increased total protein (192.8 mg/L), leucocytes: 2.6 cells/µL, positive Ig for SARS-CoV-2, negative SARS-CoV-2 PCR Demyelinating\nAIDP NA NA NA NA\nGutiérrez-Ortiz et al. [23] RT-PCR Lymphocytes 1000 cells/UI, CRP 2.8 mg/dl Positive anti-GD1b antibodies, other anti-ganglioside antibodies negative Increased total protein (80 mg/dl), no leucocytes, glucose\n62 mg/dl, negative SARS-CoV-2 PCR NA NA IVIG 400 mg/kg (5 days) NA After 2 weeks from admission complete resolution except anosmia, ageusia\nGutiérrez-Ortiz et al. [23] RT-PCR Leucopenia (3100 cells/µl) NA Increased total protein (62 mg/dl), WBC: 2/μl (all monocytes), glucose: 50 mg/dl, negative SARS-CoV-2 PCR NA NA None Paracetamol 2 weeks later complete neurological recovery with no ageusia, complete eye movements, and normal deep tendon reflexes\nHelbok et al. [24] Chest CT + serology (repeated negative RT-PCR) WBC 8.1G/L (normal: 4.0–10.0G/L), CRP 2.3 mg/dL, (normal: 0.0–0.5 mg/dL), fibrinogen level 650 mg/dL (normal: 210–400 mg/dL), LDH 276 U/L (normal: 100–250 U/L), erythrocyte sedimentation rate 55 mm/1 h Negative PCR for CMV, EBV, influenza virus A/B, Respiratory Syncytial Virus and IgM antibodies for Chlamydia pneumoniae and Mycoplasma pneumoniae Increased total protein (64 mg/dl), cell count: 2 cells/mm3, serum/ CSF glucose ratio of 0.83, negative SARS-CoV-2 PCR, positive anti-SARS-CoV-2 antibodies (not determined if intrathecal synthesis or passive transfer from blood) Demyelinating with sural sparing\nAIDP Spinal: no pathological findings IVIG 30 g + plasma exchange (4 cycles) + mechanical invasive ventilation None Improvement of muscle forces with recovery of mobility without significant help after 8 weeks\nHutchins et al. [25] RT-PCR + chest CT Lymphopenia (absolute lymphocyte count of 0.7 K/mm3) Serum HSV IgG and IgM. Respiratory viral panel PCR negative Negative GM1, GD1b, and GQ1b IgG and IgM), aquaporin-4 receptor (IgG), HIV 1/2, HSV 1/2 (IgG and IgM), CMV (IgM), Mycoplasma pneumoniae (IgG and IgM), Borrelia burgdorferi (IgG and IgM), Bartonella species (IgG and IgM), and syphilis (Venereal Disease Research Laboratory test) Increased total protein (49 mg/dL), normal glucose levels (65 mg/dL), no leukocytes Mixed demyelinating and axonal EMG subtype unknown Brain: enhancement of the facial and abducens nerves bilaterally, as well as the right oculomotor nerve\nSpinal: no pathological findings Plasma exchange (5 cycles) NA Discharged to inpatient rehabilitation\nJuliao Caamaño et al. [26] RT-PCR NA NA Normal total protein (44 mg/dL), no pleocytosis Absent blink-reflex\nEMG subtype unknown Brain: no pathological findings Oral prednisolone Hydroxychloroquine and lopinavir/ritonavir for 14 days Minimal improvement of muscle weakness after 2 weeks\nKhalifa et al. [27] RT-PCR + chest X-ray + chest CT WBC 5.5 × 103, PC 356 × 103, CRP 0.5 mg/dL (normal 0.0–0.5), serum ferritin 87.3 ng/ml (normal 12.0–150.0), elevated d-Dimer levels 0.72 mg/L (0.00–0.49) Negative screening for:  influenza A and B viruses; influenza A virus subtypes H1, H3, and H5 including subtype H5N1 of the Asian lineage; parainfluenza virus types 1, 2, 3, and 4; respiratory syncytial virus types A and B; adenovirus; metapneumovirus; rhinovirus; enterovirus; Coronavirus 229E, HKU1, NL63, and OC43 Cell count: 5 mm3, increased total protein (316.7 mg/dL) Demyelinating\nAIDP Brain: no pathological findings\nSpinal: enhancement of the cauda equina nerve roots IVIG 1 g/kg (2 days) Paracetamol, azithromycin, hydroxychloroquine Discharge to home after 15 days with clinical and electrophysiological improvement\nKilinc et al. [28] Fecal PCR + serology NA Negative anti-GQ1b antibodies, serologic tests on Borrelia burgdorferi, syphilis, Campylobacter jejuni, CMV, hepatitis E, Mycoplasma pneumoniae and CMV Normal cell count, normal proteins Predominantly demyelinating\nAIDP Brain: no pathological findings IVIG 2 g/kg (5 days) None Persistence of mild symptoms at the discharge (after 14 days)\nLampe et al. [29] RT-PCR (negative chest X-ray) Slightly increased CRP (1.92 mg/dL) Negative anti-ganglioside antibodies; negative influenza and respiratory syncytial virus Increased total protein (56 mg/dL), normal cell count (2 cells/μL) Demyelinating\nAIDP NA IVIG 400 mg/kg (5 days) None Improvement of GBS symptoms with persistence of generalized areflexia except for left biceps reflex, discharge after 12 days\nLantos et al. [30] RT-PCR NA GM1 antibodies in the equivocal range NA NA Brain: enlargement, prominent enhancement with gadolinium, and T2 hyperintense signal of the left cranial nerve III IVIG Hydroxychloroquine Improvement, discharge after 4 days\nLascano et al. [31] RT-PCR + chest X-ray + positive IgM (IgG positivity 2 weeks later) WBC 8900 cells/mm3; lymphocytes 1200 cells/mm3; PC 45,500 cells/mm3 Negative anti-ganglioside antibodies Increased total protein (60 mg/dL), leucocytes: 3 cells/μL, negative SARS-CoV-2 PCR Demyelinating\nAIDP Spinal: no nerve root gadolinium enhancement IVIG 400 mg/kg (5 days) + mechanical\ninvasive ventilation Azithromycin Improvement of tetraparesis.\nAble to stand up with assistance.\nLascano et al. [31] RT-PCR + chest X-ray WBC 3300 cells/mm3; lymphocytes 800 cells/mm3; PC 119,000 cells/mm3 NA Normal total protein (40 mg/dl), cell count: 2 cells/μL Mixed demyelinating (conduction blocks) and axonal with sural sparing pattern\nPredominantly AIDP NA IVIG 400 mg/kg (5 days) Amoxicillin, clarithromycin Dismissal with full motor recovery. Persistence of LL areflexia and distal paraesthesia\nLascano et al. [31] RT-PCR + chest X-ray WBC 4000 cells/mm3; lymphocytes 600 cells/mm3; PC 322,000 cells/mm3 NA Increased total protein (140 mg/dL), cell count: 4 cells/μL, negative SARS-CoV-2 PCR Demyelinating with sural sparing pattern\nAIDP Brain: no pathological findings\nSpinal cord: lumbosacral nerve root enhancement IVIG 400 mg/kg (5 days) Amoxicillin Improvement of tetraparesis and ability to walk with assistance. Persistence of neuropathic pain and distal paraesthesia\nManganotti et al. [32] RT-PCR + chest CT NA Negative anti-ganglioside antibodies negative serum anti-HIV, anti-HBV, anti-HCV antibodies Increased total protein (74.9 mg/dL), negative CSF PCR for bacteria, fungi, Mycobacterium tuberculosis, Herpes viruses, Enteroviruses, Japanese B virus and Dengue viruses NA Brain: no pathological findings IVIG 400 mg/kg (5 days) Lopinavir/ritonavir, hydroxychloroquine, antibiotic therapy, oxygen support (35%) Resolution of all symptoms except for minor hyporeflexia at the LL\nManganotti et al. [33] RT-PCR IL-1: 0.2 pg/ml (\u003c 0.001 pg/ml), IL-6: 113.0 pg/ml (0.8–6.4 pg/ml), IL-8: 20.0 pg/ml (6.7–16.2 pg/ml), TNF-α: 16.0 pg/ml (7.8–12.2 pg/ml) Negative anti-ganglioside antibodies, negative HIV, HBV, HCV negative serological tests for autoimmune disorders Increased total protein (52 mg/dl), leucocytes: 1 cell/mm3, negative SARS-CoV-2 PCR Demyelinating\nAIDP NA IVIG 400 mg/kg/day (5 days) Hydroxychloroquine, oseltamivir, darunavir, methylprednisolone and tocilizumab + mechanical invasive ventilation Improvement of motor symptoms\nManganotti et al. [33] RT-PCR IL-1: 0.5 pg/ml (\u003c 0.001 pg/ml), IL-6: 9.8 pg/ml (0.8–6.4 pg/ml), IL-8: 55.0 pg/ml (6.7–16.2 pg/ml), TNF- α: 16.0 pg/ml (7.8–12.2 pg/ml) Negative anti-ganglioside antibodies, negative HIV, HBV, HCV negative serological tests for autoimmune disorders Normal total protein (40 mg/dl), leucocytes: 1 cell/mm3, negative SARS-CoV-2 PCR Mixed demyelinating and axonal   EMG subtype unknown Brain: no pathological findings IVIG 400 mg/kg/day (5 days) Hydroxychloroquine, lopinavir/ritonavir, methylprednisolone + mechanical invasive ventilation Improvement of motor symptoms\nManganotti et al. [33] RT-PCR NA Negative anti-ganglioside antibodies, negative HIV, HBV, HCV negative serological tests for autoimmune disordes Increased total protein (72 mg/dL), leucocytes: 5 cell/mm3, negative SARS-CoV-2 PCR Mainly demyelinating\nPredominantly AIDP Brain: no pathological findings IVIG 400 mg/kg/day (5 days) Hydroxychloroquine, lopinavir/ritonavir, methylprednisolone Improvement\nManganotti et al. [33] RT-PCR NA NA NA Mixed demyelinating and axonal  EMG subtype unknown NA Methylprednisolone 60 mg for 5 days Methylprednisolone Stationary\nManganotti et al. [33] RT-PCR IL-1: 0.2 pg/ml (\u003c 0.001 pg/ml), IL-6: 32.7 pg/ml (0.8–6.4 pg/ml), IL-8: 17.8 pg/ml (6.7–16.2 pg/ml), TNF- α : 11.1 pg/ml (7.8–12.2 pg/ml), IL-2R: 1203.0 pg/ml (440.0–1435.0 pg/ml), IL-10: 4.6 (1.8–3.8 pg/ml) Negative anti-ganglioside antibodies, negative HIV, HBV, HCV negative serological tests for autoimmune disordes Increased total protein (53 mg/dL), leucocytes: 2 cell/mm3, negative SARS-CoV-2 PCR Mixed demyelinating and axonal  EMG subtype unknown NA IVIG 400 mg/kg/day (5 days) Hydroxychloroquine, lopinavir/ritonavir, methylprednisolone, meropenem, linezolid, clarithromycin, fluconazole, doxycycline + mechanical invasive ventilation Improvement\nMarta-Enguita et al. [34] RT-PCR + chest CT Thrombocytopenia, d-Dimer elevation NA NA NA NA NA NA Death after 10 days\nMozhdehipanah et al. [35] RT-PCR (negative chest CT) Normal WBC, CRP and ESR NA Increased total protein (139 mg/dL), normal cell count, negative CSF HSV serology and gram stain and culture Demyelinating\nAIDP NA Plasma exchange (5 cycles) NA Significant improvement of muscle weakness after 3 weeks, persistence of mild bifacial paresis\nMozhdehipanah et al. [35] RT-PCR Normal WBC, CRP and ESR NA Albuminocytological dissociation NA NA IVIG 400 mg/kg/day (5 days) NA Complete recovery, except for the persistence of hyporeflexia\nMozhdehipanah et al. [35] RT-PCR + chest CT Leucocytosis lymphopenia, elevated ESR and CRP NA Increased total protein (57 mg/dL), normal cell count and glucose (not further specified) Axonal\nAMSAN NA IVIG 400 mg/kg/day (3 days) Hydroxy chloroquine, lopinavir/ ritonavir Death after 3 days from starting treatment with IVIG\nMozhdehipanah et al. [35] RT-PCR + chest CT Leucocytosis, lymphopenia, elevated ESR and CRP NA Increased total protein (89 mg/dL), normal cell count and glucose (not further specified) Demyelinating\nAIDP NA IVIG 400 mg/kg/day (5 days) Hydroxy chloroquine, lopinavir/ ritonavir No significant clinical improvement\nNaddaf et al. [36] Positive SARS-CoV-2 IgG (index value: 8.2, normal \u003c 0.8) and IgA + chest CT (negative RT-PCR) Normal completed blood count, elevated d-dimer (690 ng/mL), ferritin (575 mcg/L), ESR (26 mm/h), alanine aminotransferase (73 U/L) Negative anti-ganglioside antibodies negative HIV, syphilis, West Nile virus, Lyme disease testing, EBV and CMV serology consistent with remote infection, negative paraneoplastic evaluation Increased total protein (273 mg/dL), total cells count: 2/mm3, negative CSF SARS-CoV-2 RT-PCR, negative meningitis/encephalitis panel, negative oligoclonal bands and IgG index Demyelinating\nAIDP Spine: smooth enhancement of the cauda equine roots Plasma exchange (5 sessions) Hydroxy chloroquine, zinc, methylprednisolone 40 mg bid for 5 days Improvement of motor and gait examination. Persistence of slight ataxia without requiring gait aid\nOguz-Akarsu et al. [37] RT-PCR + chest MRT + chest CT Mild neutropenia (1.49 cells/µL) and a high monocyte percentage (19.77) HIV test negative Normal total protein (32.6 mg/dL) with no leucocytes Demyelinating with sural sparing pattern\nAIDP Cervical and lumbar and spine: asymmetrical thickening and hyperintensity of post-ganglionic roots supplying the brachial and lumbar plexuses in STIR sequences Plasma exchange (five sessions, one every other day) Hydroxychloroquine, azithromycin Marked neurological improvement after 2 weeks and she was able to walk without assistance\nOttaviani et al. [38] RT-PCR + chest CT Lymphopenia, increased d-dimer, CRP and CK Negative anti-ganglioside antibodies Increased total protein (108 mg/dL), cell count: 0 cells/μL Mainly demyelinating\nPredominantly AIDP NA IVIG 400 mg/kg (5 days) Lopinavir/ritonavir, hydroxychloroquine Progressive worsening with multi-organ failure\nPadroni et al. [39] RT-PCR + chest CT WBC 10.41 × 109/L (neutrophils 8.15 × 109/L), normal d-dimer Negative screening for Mycoplasma pneumonia, CMV, Legionella pneumophila, Streptococcus pneumoniae, HSV, VZV, EBV, HIV-1, Borrelia burgdorferi; auto-antibodies not performed Increased total protein (48 mg/dl), cell count: 1 × 106/L Motor sensory axonal\nAMSAN NA IVIG 400 mg/kg (5 days) + mechanical invasive ventilation NA At day 6 from admission: ICU with mechanical invasive ventilation\nPaterson et al. [40] Definite diagnosis (not specified) (normal chest CT) Increased neutrophils and CRP NA Increased total protein (0.5 g/L),\nleucocytes: 3 cells/μL (0–5), Demyelinating\nAIDP NA IVIG + mechanical invasive ventilation None 17 days of hospitalisation, at discharge able to walk 5 m (across an open space) but incapable of manual work/running\nPaterson et al. [40] Definite diagnosis (not specified) (normal chest CT) Increased CRP and fibrinogen NA Increased total protein (0.6 g/L)\nleucocytes: 2 cells/μL (0-5), Glucose 3.4 (mmol/L; 2.2-4.2) Demyelinating\nAIDP Brain: no pathological findings IVIG Mechanical invasive ventilation 46 days (ongoing) of hospitalisation, still critical and requiring ventilation\nPaterson et al. [40] Definite diagnosis (not specified) (normal chest CT) Not significant findings NA Increased total protein (0.9 g/L)\nleucocytes: \u003c 1 cells/μL (0-5), Glucose 3.7 (mmol/L; 2.2-4.2) Demyelinating\nAIDP Brain: no pathological findings IVIG NA 7 days (ongoing) of hospitalisation, able to walk 5 m (across an open space) but incapable of manual work/running\nPaybast et al. [41] RT-PCR NA NA Increased total protein (139 mg/dL), normal glucose and cell count, normal CSF viral serology, negative gram stain and culture Mixed demyelinating and axonal  EMG subtype unknown NA 5 sessions of therapeutic plasma exchange, intravenous bolus of labetalol to control sympathetic nervous system over-reactivity Hydroxychloroquine sulphate 200 mg two times per day for a week Persistence of generalized hyporeflexia, decreased light touch sensation in distal limbs, mild bilateral facial paresis, sympathetic over-reactivity successfully controlled with labetalol,\nPaybast et al. [41] RT-PCR NA NA Albuminocytological dissociation NA NA IVIG 20 g (5 days) Hydroxychloroquine sulphate 200 mg two times per day for a week Persistence of generalized hyporeflexia and decreased light touch sensation in distal limbs\nPfefferkorn et al. [42] RT-PCR + chest CT NA Negative anti-gangliosides antibodies At admission: Normal total protein, cell count: 9/µL, negative SARS-CoV-2 PCR\nAt day 13th: increased total protein (10.231 mg/L), normal cell count Demyelinating\nAIDP Spinal: massive symmetrical contrast enhancement of the spinal nerve roots at all levels of the spine including the cauda equina. Anterior and posterior nerve roots were equally affected IVIG 30 g (5 days) + mechanical invasive ventilation + plasma exchange NA At day 31 from admission: motor improvement with regression of facial and hypoglossal paresis but still needed mechanical ventilation\nRana et al. [43] RT-PCR NA NA NA Demyelinating with sural sparing\nAIDP Thoracic and lumbar spine: no evidence of myelopathy or radiculopathy IVIG 400 mg/kg (5 days) Hydroxychloroquine and azithromycin On day 4 respiratory improvement, on day 7 rehabilitation\nReyes-Bueno et al. [44] Serology (negative RT-PCR) NA Negative anti-ganglioside antibodies Increased total protein (70 mg/dl), cell count: 5 cells/µl, albuminocytological dissociation Demyelinating with alteration of the Blink-Reflex. Further EMG: polyradiculoneuropathy with proximal and brainstem involvement\nAIDP NA IVIG 400 mg/kg (5 days) + Gabapentin NA After the 18th day progressive improvement of  facial and limb paresis, diplopia and pain. Consequent neurological rehabilitation\nRiva et al. [45] Chest CT + serology (negative RT-PCR) No pathological findings Negative anti-ganglioside antibodies Normal total protein and cells; negative PCR for SARS-CoV2, EBV, CMV, VZV, HSV 1–2, HIV Demyelinating with sural sparing\nAIDP Brain: NA\nSpinal: no pathological findings IVIG 400 mg/kg (5 days) None Slowly improvement after the 10th day\nSancho-Saldaña et al. [46] RT-PCR + chest X-Ray NA Negative anti-ganglioside antibodies Increased total protein (0.86 g/L), cell count: 3 leucocytes Demyelinating\nAIDP Whole spine: brainstem and cervical meningeal enhancement IVIG 400 mg/kg (5 days) Hydroxychloroquine, azithromycin Recovering by day 7 after the onset of weakness.\nScheidl et al. [47] RT-PCR No pathological findings Negative Campylobacter Jejuni and Borrelia serology, negative ANA, anti-DNA, c-ANCA,p-ANCA Increased total protein (140 g/L), albuminocytological dissociation Demyelinating\nAIDP Brain: NA\nCervical spine: no pathological findings IVIG 400 mg/kg (5 days) None Complete recovery\nSedaghat et al. [48] RT-PCR + chest CT Increased WBC 14.6 × 103 (neutrophils 82.7%, lymphocytes 10.4%) and CRP NA NA Motor sensory Axonal\nAMSAN Brain: no pathological findings\nSpinal: two cervical intervertebral disc herniations IVIG 400 mg/kg (5 days) Hydroxychloroquine, lopinavir/ritonavir, azithromycin Not reported\nSidig et al. [49] RT-PCR + chest CT NA NA None Demyelinating\nAIDP Brain: no pathological findings NA NA Death after 7 days; because of progressive respiratory failure\nSu et al. [50] RT-PCR + chest X-ray WBC 12,000 cells/µl Negative anti- ganglioside GM1, GD1b and GQ1b antibodies, acetylcholine receptor binding, voltage-gated calcium channel, antinuclear and ANCA Increased total protein (313 mg/dL), WBC: 1 cell Demyelinating\nAIDP NA IVIG 2gm/kg (for 4 days) None On day 28 persistence of severe weakness\nTiet et al. [51] RT-PCR Elevated lactate on venous blood gas (3.3 mmo/L), mildly elevated CRP (20 mg/L). Normal WBC, sodium, potassium and renal function. NA Increased total protein (\u003e 1.25 g/L), cell count 1x106/L Demyelinating\nAIDP NA IVIG 400 mg/kg/day (5 days) None Resolution of facial diplegia, improved upper and lower limbs weakness; able to mobilize unassisted 11 weaks after neurorehabilitation\nToscano et al. [52] RT-PCR + Chest CT + serology Lymphocytopenia, increased CRP, LDH, ketonuria Negative anti-ganglioside antibodies Day 2: normal total protein, no cells, negative SARS-CoV-2 PCR\nDay 10: increased total protein (101) mg/dl, cell count: 4/mm3, negative SARS-CoV-2 PCR Axonal with sural sparing\nAMSAN Brain: no pathological findings\nSpinal: Enhancement of caudal nerve roots IVIG 400 mg/kg (2 cycles) + temporary mechanical non-invasive ventilation Paracetamol At week 4 persistence of severe UL weakness, dysphagia, and LL paraplegia\nToscano et al. [52] RT-PCR (negative chest CT) Lymphocytopenia; increased ferritin, CRP, LDH NA Increased total protein (123 mg/dl), no cells, negative SARS-CoV-2 PCR Motor sensory axonal with sural sparing\nAMSAN Brain: enhancement of facial nerve bilaterally\nSpinal: no pathological findings IVIG 400 mg/kg Amoxycillin At week 4 improvement of  ataxia and mild improvement of  facial weakness\nToscano et al. [52] RT-PCR + chest CT Lymphocytopenia; increased CRP, LDH, ketonuria Negative anti-ganglioside antibodies Increased total protein (193 mg/dl), no cells, negative SARS-CoV-2 PCR Motor axonal\nAMAN Brain: no pathological findings\nSpinal: enhancement of caudal nerve roots IVIG 400 mg/kg (2 cycles) + mechanical invasive ventilation Azythromicin ICU admission due to respiratory failure and tetraplegia. At week 4 still critical\nToscano et al. [52] RT-PCR + serology (negative chest CT) Lymphocytopenia; increased CRP, ketonuria NA Normal protein, no cells, negative SARS-CoV-2 PCR Demyelinating\nAIDP Brain: no pathological findings\nSpinal: no pathological findings IVIG 400 mg/kg None At week 4 mild improvement in UL but unable to stand\nToscano et al. [52] Chest CT + serology (negative RT-PCR in nasopharyngeal swab and BAL) Lymphocytopenia; increased CRP, LDH Negative anti-ganglioside antibodies; negative screening for Campylobacter jejuni, EBV, CMV, HSV, VZV, influenza, HIV Normal total protein (40 mg/dL), white cell count 3/mm3; negative SARS-CoV-2 PCR Demyelinating\nAIDP Brain: NA\nSpinal: no pathological findings IVIG 400 mg/kg + plasma exchange + mechanical invasive ventilation + enteral nutrition None At week 4 flaccid tetraplegia, dysphagia, ventilation dependent\nVelayos Galán et al. [53] RT-PCR + chest X-ray NA NA NA Demyelinating\nAIDP NA IVIG 400 mg/kg (5 days) Hydroxychloroquine, lopinavir/ritonavir, amoxicillin, corticosteroids + low-flow oxygen therapy NA\nVirani et al. [54] rt-pcr + chest mrt WBC 8.6 × 103; Hb 15.4 g/dl; PC 211 × 103; procalcitonin: 0.15 ng/ml NA NA NA Brain: NA\nSpinal: no pathological findings IVIG 400 mg/kg (5 days) + mechanical invasive ventilation (4 days) Hydroxychloroquine 400 mg bid for first 2 doses, then 200 mg bid for 8 doses At day 4 of IVIG: liberation from mechanical ventilation, resolution of UL symptoms, persistence of LL weakness. Sent to a rehabilitation facility\nWebb et al. [55] RT-PCR + chest X-ray + chest CT Lymphopenia (0.9 × 109/L), thrombocytosis (490 × 109/L) raised CRP (25 mg/L) Negative ANA, ANCA, anti-ganglioside antibodies, syphilis serology HIV, hepatitis B and hepatitis C Increased total protein (0.51 g/L), normal glucose and cell count, negative SARS-CoV-2 PCR, negative viral PCR Demyelinating\nAIDP NA IVIG 400 mg/kg/day (5 days) + Mechanical invasive\nventilation Co-amoxiclav After 1 week in ICU: no oxygen requirement and ventilation\nZhao et al. [56] RT-PCR + chest CT WBC 0.52 × 109; PC 113 × 109/L NA Increased total protein (124 mg/dL), cell count 5 × 106/L Demyelinating\nAIDP NA IVIG (dosing not reported) Arbidol, lopinavir/ ritonavir At day 30 resolution of neurological and respiratory symptoms\nAIDP, acute inflammatory demyelinating polyneuropathy; AMAN, acute motor axonal neuropathy; AMSAN, acute motor sensory axonal neuropathy; ANA, antinuclear antibodies; ANCA, anti-neutrophil cytoplasmic antibodies; BAL, bronchoalveolar lavage; CK, creatine kinase; CMV, cytomegalovirus; COPD, chronic obstructive pulmonary disease, COVID-19, coronavirus disease 2019; CRP, C-reactive protein; CSF, cerebrospinal fluid; CT, computed tomography; DM, diabetes mellitus; EBV, Epstein–Barr virus; ESR, erythrocyte sedimentation rate; F, female; GBS, Guillain–Barré syndrome; GGT, gamma-glutamyl transferase; GOT, glutamic oxaloacetic transaminase; GPT, glutamate pyruvate transaminase; Hb, haemoglobin; HIV, human immunodeficiency virus; HSV, herpex simplex virus; ICU, intensive-care unit; IL, interleukin; IVIG, intravenous immunoglobulins; IL, interleukin; LDH, lactate dehydrogenase; LL, lower limbs; M, male; MRI, magnetic resonance imaging; NA, not available; PC, platelet count; PCR, Polymerase Chain Reaction; SARS-CoV-2, severe acute respiratory syndrome coronavirus-2; TNF, tumor necrosis factor; UL, upper limbs; VDRL, Veneral Disease Research Laboratory; VZV, varicella-zoster virus; WBC, white blood cells; X-ray: radiography\naTime to Nadir refers to days elapsed between the onset of neurological symptoms and the development of the worst clinical picture when no progression was reported nadir was considered concomitant with GBS symptoms onset\nbAccording to Brighton diagnostic criteria [66]\nInterestingly, patients with no improvement or poor outcome (n = 19) showed a slightly higher (but not significant) frequency of clinical history and/or a radiological picture of COVID-19 pneumonia (14/19, 73.7%) compared to those with a favorable prognosis (29/48, 60.4%, p = 0.541). Moreover, the former group of patients was significantly older (mean 62.7 ± 17.8 years, p = 0.011), but with comparable distribution of sex (p = 0.622) and electrophysiological subtypes (p = 0.144) and similar latency between COVID-19 and GBS (p = 0.588) and nadir (p = 0.825), compared to the latter (mean age 51.8 ± 16.6 years). The same findings were confirmed even after excluding cases with no improvement from the analysis (to prevent a possible bias related to the short follow-up time).\n\nDiscussion\nCOVID-19 pandemic prompts all efforts for the early recognition and treatment of its manifestations. In analogy to other viruses, belonging or not to the coronavirus family [63, 67], neurologic complications in COVID-19 are emerging as one of the most significant clinical chapters of this pandemic. In this regard, peripheral and central nervous system damage in COVID-19 has been postulated to be the consequence of two different mechanisms: 1) hematogenous (infection of endothelial cells or leucocytes) or trans-neuronal (via olfactory tract or other cranial nerves) dissemination to central nervous system in relation with viral neurotropism, and 2) abnormal immune-mediated response causing secondary neurological involvement [62, 68, 69]. The first mechanism is supposed to be responsible for the most common neurological symptoms developed by patients with COVID-19 (e.g., hypogeusia, hyposmia, headache, vertigo, and dizziness). In contrast, the second can lead to severe complications during or after the course of the illness, either dysimmune (e.g., myelitis, encephalitis, GBS) or induced by cytokine overproduction (hypercoagulable state and cerebrovascular events) [68, 69].\nIn the present systematic review, we reviewed clinical features, results of diagnostic investigations, and outcome in 73 cases of COVID-19-associated GBS spectrum [5–56].\nIn the present study, mean age at onset in patients with GBS largely overlapped that of classic COVID-19 subjects [70, 71]. However, pediatric cases with GBS have been increasingly reported in the literature [21, 27, 35, 41], suggesting that, with the spreading of the pandemic, a broader age range might be affected. Moreover, we found a higher prevalence of GBS in males compared to females, as previously reported for Zika virus–GBS [72]. This finding may also reflect the gender epidemiology of SARS-CoV-2. In this regard, males typically show a worse COVID-19 outcome compared to the females [70, 71], possibly due to a generally shorter life expectancy or to higher circulating Angiotensin-Converting-Enzyme 2 (ACE2) levels, the cellular receptor for SARS-CoV-2, in the former compared to the latter [71]. Moreover, given that GBS is a rare disease [57] the epidemiological distribution of the reported cases seems to reflect current worldwide outbreaks, with Europe being the “hottest” spot in March–May 2020 and USA together with Asia in the following period [73, 74]. On another issue, despite a few GBS cases seemed to have a para-infectious profile [10, 37, 38, 40, 55, 56] as described for Zika virus [75], all other reported patients developed neurological symptoms with a typical latency after COVID-19 (median time 14 days). This feature, together with the frequently reported negative nasopharyngeal swab at GBS onset [22, 24, 36, 44, 45, 52] and clinical improvement after IVIG therapy, seems to support the notion of a prominent post-infectious immune-mediated mechanism. However, in this context, the massive release of cytokines in COVID-19 may also contribute to the amplification of the dysimmune process underlying GBS [76, 77]. In this regard, the increase of blood inflammatory markers (e.g., CRP, IL-6, TNF-α, IL-1, etc.) in GBS tested cases may reinforce the hypothesis of a systemic inflammatory storm in COVID-19 [76, 77]. However, given the limited data, we could not perform an accurate analysis of the distribution and, eventually, prognostic value of inflammatory markers in COVID-19-associated GBS. Moreover, we cannot exclude that in cases with GBS developing before or together with COVID-19 symptoms, the disease might have progressed sub-clinically in the early phase to manifest afterwards with its typical systemic clinical picture. Indeed, two cases [10, 12], who tested positive for SARS-CoV-2, never developed COVID-19 respiratory or systemic symptoms and one of them showed an asymptomatic pneumonia at chest-CT [12]. However, only more extensive epidemiological and translational studies, with the aim to compare the characteristics of GBS associated or not with COVID-19, could clarify these issues.\nIn our population, most common clinical manifestations and distribution of clinical variants resemble those of classic GBS confirming the predominance of the sensorimotor syndrome compared to MFS and other rare variants [57–59, 66]. Similarly, the results of CSF analysis reflected typical neurochemical findings in non-COVID-19 GBS. In the latter, elevated CSF proteins and pleocytosis were described in about 50–80% [57, 78] and 11–15% cases, respectively [58, 79, 80], largely overlapping with the percentages in our cohort. In this regard, the mostly normal cell count, together with the absence of SARS-CoV-2 RNA in all tested CSF samples [6–9, 12–14, 16, 21–24, 31, 33, 36, 42, 44, 52, 55], makes the possibility of a direct invasion from SARS-CoV-2 into the nerve roots with intrathecal viral replication less probable. However, a possible bias might rely on the lack of systematic data concerning the latency between symptom onset and CSF sampling in COVID-19 GBS cases. On another issue, in a further case of MFS associated withCOVID-19, who came to our attention, we observed the absence of intrathecal synthesis of SARS-CoV-2 antibodies together with a massive increase of CSF phosphorylated neurofilament heavy chain (pNfH) and serum neurofilament light chain (NfL) proteins, supporting the role of neurochemical markers as easily implementable tools for the detection of nervous system affection in COVID-19-related diseases [81, 82].\nAt variance with CSF findings, we found a discrepancy concerning MRI findings between classic GBS and COVID-19-related GBS. Specifically, while most cases of the former group showed typically spinal root enhancement at MRI [83], in the latter group, in analogy with Zika-associated GBS, the same finding was less frequently reported [84]. However, caution should be warranted in the interpretation of these results, given that MRI findings might have been underestimated, due to lack of a sufficient number of exams in the context of pandemic-imposed restrictions in the routine clinical setting.\nRegarding the distribution of GBS electrophysiological variants, our analysis showed that COVID-19-associated GBS manifests prevalently with AIDP and, to a lesser extent, with AMSAN and AMAN, in line with classic GBS in Western countries [66, 85]. Conversely, the observation of positive anti-GD1b antibodies  in one COVID-19-related MFS patient and negative anti-ganglioside antibodies in other five cases appear in discordance with the high prevalence (≈ 90%) of anti-GQ1b antibodies among non-COVID-19 MFS cases [86], and may suggest different immune-mediated mechanisms. However, these results could not be generalized until a wider population would be tested.\nIn analogy to classic GBS, approximately one-fifth of COVID-19-associated GBS subjects required mechanical ventilation during hospitalisation [87]. In this regard, cases with no improvement or unfavorable outcome showed, in comparison to those with a good prognosis, an older age, confirming similar findings both in classic GBS [58, 88] and in COVID-19 [89], and a slightly higher frequency (without reaching a statistical significance) of past or concurrent COVID-19 pneumonia. However, given the short follow-up time in most cases, we could not reach a definite conclusion on the impact of past or concurrent COVID-19 restrictive syndrome due to pneumonia on the prognosis of GBS patients. Future prospective studies are needed to clarify this issue. Moreover, given that also preceding diarrhea (mostly caused by Campylobacter Jejuni infection) is a strong negative prognostic factor in classic GBS [57, 88], further prospective studies are needed to compare the severity of GBS related to COVID-19 to that associated with C. jejuni. Finally, in the context of respiratory failure and ventilation associated with COVID-19, the differential diagnosis should always take into consideration critical illness neuropathy and myopathy, which tend to develop later during the critical course [90]. Despite these findings, approximately one-third of COVID-19-related GBS patients showed no clinical and/or radiological evidence of pneumonia, providing evidence that GBS may also develop in the context of a paucisymptomatic or even asymptomatic COVID-19. However, given that among the GBS population only two asymptomatic COVID-19 patients were reported to date, we may speculate that, in most cases, a certain degree of lung injury (even minimal) or at least hematic dissemination (e.g., fever underlying significant viral load) is necessary to trigger the immuno-mediated process through lymphocytic recognition of self-antigens or molecular mimicry.\nMajor strengths of our review are the inclusion of a high number of patients, together with an in-depth analysis of the clinical and diagnostic features of COVID-19-associated GBS. We are aware that selection bias might have occurred, given that most reported cases to date have been described mostly in Europe (47 out of 73) and during COVID-19 highest spreading. Therefore, future extensive epidemiological studies are necessary to ascertain the nature of the association between COVID-19 and GBS (causal or coincidental). Moreover, we cannot exclude the possibility that at least some of the cases represent instances of CIDP, given the frequent absence of a follow-up longer than 2 months. On another issue, the low but possible evidence of an epidemiological link between vaccines and GBS development [57, 58] should aware the clinicians of the possible occurrence of GBS after COVID-19 vaccination in the long-term future.\nIn conclusion, based on the systematic review of 73 cases, we showed that the clinical picture of COVID-19-associated GBS seems to resemble that of classic GBS or Zika-associated GBS. Moreover, the chronological evolution, the response to IVIG, and the absence of SARS-CoV-2 RNA in CSF may suggest a prominent post-infectious immune-mediated mechanism rather than a para-infectious one. Although most cases were symptomatic for COVID-19, the preliminary report of a few patients without respiratory or systemic symptoms raises a significant healthcare issue, namely the importance of SARS-CoV-2 testing in all patients with suspected GBS during the pandemic, with the aim to provide an eventual rapid case isolation. Nevertheless, only further analyses on more comprehensive cohorts could help in clarifying better all these issues.\n\nAcknowledgements\nOpen Access funding provided by Projekt DEAL. This work was in part supported by a COVID-19 grant from the state Baden-Württemberg.\n\nAuthors’ contributions\nConceptualization: all authors; methodology, formal analysis, and investigation: Samir Abu-Rumeileh, Ahmed Abdelhak, and Matteo Foschi; writing—original draft preparation: all authors; figure preparation: Matteo Foschi; writing—review and editing: all authors; supervision: Markus Otto and Hayrettin Tumani.\n\nCompliance with ethical standards\n\nConflicts of interest\nThe authors declare that they have no conflict of interest related to the content of this article.\n\nEthical standard\nFor the present study, no authorization to an Ethics Committee was asked, because the original reports, nor this work, provided any personal information of the 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