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Guillain-Barré syndrome associated to COVID-19 infection: a review of published case reports

P. Zuberbühler, M.E. Conti, L. León-Cejas, F. Maximiliano-González, P. Bonardo, A. Miquelini, J. Halfon, J. Martínez, M.V. Gutiérrez, R. Reisin   Journal 72(06)Publication date 16/03/2021 ● RevisiónViews 42839 ● Downloads 645 Castellano English

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[REV NEUROL 2021;72:203-212] PMID: 33710610 DOI: https://doi.org/10.33588/rn.7206.2020487

INTRODUCTION. The coronavirus disease 2019 (COVID-19) pandemic is a major worldwide health disorder. There is an increasing number of neurological complications recognized with COVID-19 including patients with GBS and its variants. DEVELOPMENT. A review of the clinical cases of GBS associated to COVID-19 infection published in the last months has been developed. We included 48 patients (31 men, mean age 56.4 years). The most common COVID-19 symptoms were cough (60.4%) and fever (56.3%). Mean time from COVID-19 symptoms to neurologic manifestations was 12.1 days, but in nine patients (18.8%) developed GBS within seven days. Eleven patients (22.9%) presented cranial nerve involvement in the absence of muscle weakness; 36 presented the classic sensory motor variant (75%) and one had a pure motor variant (2.1%). The electrodiagnostic pattern was considered demyelinating in 82.4% of the generalized variants. The presence of hyposmia/dysgeusia was associated with a latency shorter than seven days to GBS onset of symptoms (30% vs 15.6%), and cranial nerve involvement in the absence of weakness (30.8% vs 17.1%). Most patients (87.5%) were treated with intravenous immunoglobulin. Neurological outcome was favorable in 64.6%; 29.2% had respiratory failure and 4.2% died shortly after being admitted.

CONCLUSIONS. GBS in patients with SARS-CoV-2 infection resembles clinically and electrophysiology the classical forms. Further studies are necessary to understand whether GBS frequency is actually increased due to SARS-CoV-2 infection and explore pathogenic mechanisms.

Acute inflammatory demyelinating polyneuropathy Acute motor axonal neuropathy Acute motor sensory axonal neuropathy Bilateral facial palsy COVID-19 Guillain-Barré syndrome Miller Fisher syndrome SARS-CoV-2 Infecciones Nervios periféricos, unión neuromuscular y músculo

Introduction 


The first report of the novel coronavirus infection was on 31 December 2019 in Wuhan, Hubei Province, China [1]. Since then the virus has rapidly spread around the world, and on February 11th, 2020, the World Health Organization (WHO) named this new infection as coronavirus disease 2019 (COVID-19). At the same time, the International Committee on Taxonomy of Viruses renamed the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), and in March 2020 it was defined as a pandemic. Similar to other coronaviruses, COVID-19 mainly affects the respiratory tract after an incubation period of 3 to 14 days. Depending on the patient’s immune system and comorbidities, the symptoms may remain mild or lead to severe progression and even death. The most common manifestations of COVID-19 are fever, cough, dyspnea, pneumonia and respiratory complications. However, gastroenterological and neurological manifestations have been also described [2,3]. Neurologic symptoms are present in about 57% of patients, including mild symptoms such as hyposmia, dysgeusia, myalgias and headache, which appear at an early stage of the disease, and other symptoms that usually appear in patients with more advanced disease associated to moderate or severe infection (depressed levels of consciousness, confusion, seizures, stroke and encephalitis) [4]. Guillain-Barré syndrome (GBS) is an acute inflammatory polyradiculoneuropathy and the most common cause of flaccid paralysis in the world. Patients with GBS typically present with painful paresthesias and ascending symmetric weakness, with reduced or absent tendon reflexes. Patients can also have cranial nerves involvement and respiratory muscle weakness. The clinical presentation of the disease is heterogeneous, and several variants exist [5-7].

GBS pathogenesis represents an infectious-triggered autoimmune disease. Several pathogens have been associated with GBS, including virus such as influenza, enteroviruses, cytomegalovirus, Epstein-Barr, herpes simplex, hepatitis, and HIV [7]. GBS outbreaks have been also associated with viral epidemics, including H1N1, dengue, chikungunya and Zika virus, and with coronavirus, including the Middle East respiratory syndrome (MERS)-CoV and SARS-CoV.

The cross-immunity between viral antigens and peripheral nerve glycolipids has not been well characterized [8]. Neurotrophic characteristics of coronavirus have been described previously, but the exact mechanism of damage is yet to be elucidated [9].

Up to July 4, 2020, 47 patients have been reported with classical GBS or its variants, in association with COVID-19 infection. Moreover, it has been suggested an increase in the frequency of GBS associated with the current pandemic [10].
 

Development


We made a retrospective review of the published literature of GBS associated with COVID-19 infection identified via PubMed using the following search terms: ‘Guillain-Barré’, ‘acute inflammatory demyelinating polyneuropathy’, ‘acute motor axonal neuropathy’, ‘acute motor sensory axonal neuropathy’ or ‘Miller Fisher’ and ‘SARS-CoV-2’ or ‘COVID’. The last article included was published on July 4, 2020. We selected articles both in English and in Spanish language, and we chose ‘title’ as search field. We included only patients who have had a COVID-19 infection confirmed either by reverse transcription polymerase chain reaction (RT-PCR) for SARS-CoV-2 or with positive COVID-19 serum antibodies (IgM/IgG). We registered epidemiologic data such as gender, age, COVID-19 symptoms, COVID test performed, time gap between the COVID-19 infection and the first GBS symptom, neurological manifestations, anti-gangliosides, CSF characteristics, EMG results (when available), GBS variant, treatment and outcome.

We analized 47 patients from 37 articles and an additional patient who was admitted in our center (48 patients: 31 men, mean age 56.4 years, range 14-77 years) with GBS or its variants [11,12], associated with SARS-CoV-2 infection (Table I). The reports included 12 patients from Italy, nine from Spain, five from USA, four from France, four from Iran, two from Germany and one from Canada, Morocco, the UK, the Netherlands, Turkey and China.

 

Table I. Demographic, clinical, CSF and neurophysiological findings in patients with GBS associated to COVID-19.

Pt #

Authors

Sex/Age

Covid-19 symptoms

COVID test

Time gap

Neurological manifestations and outcome

Anti-gan­gliosides

CSF

EMG (Electrophysio­logical subtype)

GBS variant

Treatment

1

Zuberbühler et al

F/72

Rhino conjunctivitis

IgG+ PCR-

5 days

Bilateral PFP (Left first), dysgeusia, anosmia, LL paresthesias, ataxic gait

Neg

Mild pleocytosis

PCR-

Reduced UL sensory CVs

Facial diplegia & paresthesias

Not treated

2

Chan et al [13]

M/ 58

Asymptomatic

PCR+

Contact 20 days

Bilateral PFP, dysarthria, areflexia, paresthesias distal LL

NA

ACD, PCR-

Blink reflex NR; F wave NR

Facial diplegia & paresthesias

IVIG

3

Caamaño et al [14]

M/ 61

Cough, fever

PCR+

10 days

Bilateral PFP

NA

ACD, PCR-

NA

Facial diplegia

Not treated

4

Lantos et al [15]

M/ 36

Fever, myalgias

PCR+

2 days

Cranial nerve III & VI bilateral palsy, areflexia, hypoesthesia and paresthesias LL, ataxia

Anti-GM1 + (equivocal range)

NA

NA

Miller Fisher syndrome

IVIG

5

Reyes Bueno, et al [16]

F/51

Diarrhea, odynophagia, cough

IgG+ PCR-

14 days

Left III cranial nerve paresis, diplopia, inferior bilateral facial paresis, areflexia, autonomic dysfunction

Neg

ACD

Blink reflex NR; prolonged F waves

Miller Fisher syndrome

IVIG

6

Gutierrez-Ortiz et al [17]

M/ 50

Cough, headache, fever, anosmia, ageusia

PCR+

3 days

Right ophthalmoplegia, perioral paresthesias, areflexia, gait ataxia

Anti GD1b-IgG +

NA

NA

Miller Fisher syndrome

IVIG

7

Gutierrez-Ortiz et al [17]

M/ 39

Diarrhea, fever, ageusia

PCR+

3 days

Bilateral ophthalmoplegia, areflexia

NA

ACD

NA

Miller Fisher syndrome

Not treated

8

Manganotti, et al [18]

M/50

Fever, cough, hypogeusia

PCR+

16 days

Ophthalmoplegia, areflexia, ataxia

Neg

ACD, PCR -

NA

Miller Fisher syndrome

IVIG

9

Fernández-Domínguez et al [19]

F/ 74

Bilateral pneumonia

PCR+

24 days

Gait ataxia, LL areflexia

Neg

ACD

F-wave delay UL

Miller Fisher like síndrome

IVIG

10

Assini et al [20]

M/ 55

Anosmia, ageusia, fever, cough, SARS

PCR+

20 days

Bilateral ptosis, dysphagia and dysphonia (IX-X palsy), hyporeflexia

Neg

OCB; PCR-

Demyelinating neuropathy

Cranial polyneuritis

IVIG

11

Paybast et al [21]

M/ 38

Upper respiratory tract infection

PCR+

16 days

Bilateral PFP, areflexia, ascending paresthesias, distal hypoesthesia 4L; later dysphagia (IX-X palsy)

NA

ACD, PCR-

Demyelinating neuropathy

Cranial polyneuritis

IVIG

12

Hutchins, et al [22]

M/21

Fever, cough, dyspnea, diarrhea, nausea, headache

PCR +

16 days

Bilateral PFP, hypogeusia, proximal weakness 4L, areflexia, UL paresthesias

Neg

ACD

Mixed pattern (Equivocal)

Classic sensorymotor

Plasma exchange

13

El Otmani et al [23]

F/ 70

Dry cough

PCR+

2 days

Acute flaccid areflexic tetraplegia and paresthesia

NA

ACD

Axonal neuropathy (AMSAN)

Classic sensorymotor

IVIG

14

Bigaut et al [24]

M/ 43

Cough, asthenia, myalgia, anosmia, ageusia, diarrhea

PCR+

21 days

Right PFP, distal weakness in LL, areflexia, paresthesia, hypoesthesia, ataxia

NA

ACD

Demyelinating neuropathy (AIDP)

Classic sensorymotor

IVIG

15

Bigaut et al [24]

F/ 70

Asthenia, myalgia, anosmia, ageusia, diarrhea

PCR+

7 days

Left PFP, proximal acute tetraparesis, areflexia, distal and perioral paresthesias

NA

ACD

Demyelinating neuropathy (AIDP)

Classic sensorymotor

IVIG

16

Sedaghat et al [25]

M/ 65

Cough, fever, dyspnea

PCR+

14 days

Bilateral PFP, acute ascending tetraparesis, areflexia, distal hypoesthesia LL

NA

NA

Axonal neuropathy (AMSAN)

Classic sensorymotor

IVIG

17

Camdesan­che et al [26]

M/ 64

Cough, fever

PCR+

11 days

Dysphagia, flaccid tetraparesis, areflexia, distal paresthesias
Respiratory failure (MV)

Neg

ACD

Demyelinating neuropathy (AIDP)

Classic sensorymotor

IVIG

18

Assini et al [20]

M/ 60

Fever, cough, SARS

PCR+

20 days

Acute distal weakness LL, areflexia, gastroparesis, arterial hypotension

Neg

OCB; PCR-

Axonal neuropathy (AMSAN)

Classic sensorymotor

IVIG

19

Scheidl et al [9]

F/ 54

Hyposmia, hypogeusia

PCR+

11 days

Acute paraparesis, areflexia, hypoesthesia & paresthesias 4L

NA

ACD

Demyelinating neuropathy
(AIDP)

Classic sensorymotor

IVIG

20

Gigli et al [10]

M/ 53

Fever, diarrhea

IgM/G+ PCR-

NA

Paresthesias, ataxia

Neg

ACD

Demyelinating neuropathy
(AIDP)

Classic sensorymotor

IVIG

21

Ottaviani et al [27]

F/ 66

Fever, cough

PCR+

10 days

Unilateral PFP, Paraplegia, brachial diparesis, areflexia
Respiratory failure (MV)

Neg

ACD

Demyelinating neuropathy
(AIDP)

Classic sensorymotor

IVIG

22

Zhao et al [28]

F/ 61

Arrived from Wuham asymptomatic

PCR+

0

Tetraparesis, areflexia, distal hypoesthesia

NA

ACD

Demyelinating neuropathy (AIDP)

Classic sensorymotor

IVIG

23

Virani et al [29]

M/ 54

Dry cough, diarrhea

PCR+

10 days

Mild tetraparesis, areflexia, paresthesias
Respiratory failure (MV)

NA

NA

NA

Classic sensorymotor

IVIG

24

Coen et al [30]

M/ 70

Dry cough, myalgia, fatigue

PCR+

6 days

Flaccid tetraparesis, areflexia, distal allodynia

Neg

ACD

Demyelinating neuropathy (AIDP)

Classic sensorymotor

IVIG

25

Padroni et al [31]

F/ 70

Fever, dry cough

PCR+

24 days

Tetra paresis, areflexia, distal paresthesias, gait disturbances
Respiratory failure (MV)

NA

ACD

Demyelinating neuropathy (AIDP)

Classic sensorymotor

IVIG

26

Arnaud et al [32]

M/ 64

Cough, dyspnea, diarrhea, fever

PCR+

23 days

Flaccid paraparesis, areflexia, hypoesthesia 4L

Neg

ACD

Demyelinating neuropathy (AIDP)

Classic sensorymotor

IVIG

27

Su et al [33]

M/ 72

Diarrhea, anorexia, chills

PCR+

6 days

Tetraparesis, areflexia, distal hypoesthesia, paresthesias, dysautonomia
Respiratory failure (MV)

Neg

ACD, PCR-

Demyelinating neuropathy (AIDP)

Classic sensorymotor

IVIG

28

Toscano et al [34]

F/ 77

Fever, cough, ageusia

PCR+

7 days

Bilateral PFP, tetraplegia, areflexia, paresthesias
Respiratory failure (NIV)

Neg

ACD, PCR-

Axonal neuropathy (AMSAN)

Classic sensorymotor

IVIG 2 cycles

29

Toscano et al [34]

M/ 23

Fever, odynophagia

PCR+

10 days

Bilateral PFP, areflexia, paresthesias, ataxia

NA

ACD, PCR-

Axonal neuropathy (AMSAN)

Classic sensorymotor

IVIG

30

Toscano et al [34]

M/ 76

Dry cough, anosmia

PCR+

4 days

Tetraplegia, areflexia, ataxia

NA

Normal (5 day)

Demyelinating neuropathy (AIDP)

Classic sensorymotor

IVIG

31

Toscano et al [34]

M/ 61

Asthenia, dry cough, anosmia, ageusia

IgG+ PCR-

7 days

Bilateral PFP, tetraplegia, areflexia, LL paresthesias
Respiratory failure (MV)

Neg

Normal, PCR-

Demyelinating neuropathy (AIDP)

Classic sensorymotor

IVIG and plasma exchange

32

Rana et al [35]

M/ 54

Rhinorrhea, odynophagia, fever, chills

PCR+

14 days

Bilateral PFP, ophtalmoparesis, tetraparesis, areflexia, paresthesias
Respiratory failure (MV)

NA

NA

Demyelinating neuropathy (AIDP)

Classic sensorymotor

IVIG

33

Riva et al [36]

M/ 60

Fever, headache, myalgia, ageusia, anosmia

IgG+ PCR-

20 days

Bilateral PFP, dysarthria, tetraplegia, paresthesias

Neg

Normal

Demyelinating neuropathy (AIDP)

Classic sensorymotor

IVIG

34

Velayos Galan et al [37]

M/ 43

Diarrhea, upper respiratory symptoms

PCR+

10 days

Bilateral PFP, dysphagia, tetraparesis, areflexia, dysesthesias

NA

NA

Demyelinating neuropathy (AIDP)

Classic sensorymotor

IVIG

35

Marta-Enguita et al [38]

F/ 76

Dry cough, fever

PCR+

8 days

Dysphagia, tetraparesis, areflexia, paresthesias, hypoesthesia

Respiratory failure (died in <24 hs)

NA

NA

NA

Classic sensorymotor

Not treated

36

Sancho-Saldaña et al [39]

F/ 56

Fever, dry cough, dyspnea

PCR+

15 days

Bilateral PFP, oropharyngeal weakness, proximal tetraparesis, paresthesia UL, ataxia

NA

ACD, PCR-

Demyelinating neuropathy
(AIDP)

Classic sensorymotor

IVIG

37

Paybast et al [21]

F/ 14

Upper respiratory tract infection

PCR+

14 days

Weakness LL, areflexia, paresthesias, hypoesthesia 4L, ataxia

NA

ACD

NA

Classic sensorymotor

IVIG

38

Helbok et al [40]

M/68

Dry cough, headache, fatigue, myalgia, fever, anosmia, ageusia

IgG+ PCR-

14 days

Ascending dysesthesias, proximal weakness 4L
Respiratory failure (MV)

Neg

ACD, IgG+

Demyelinating neuropathy (AIDP)

Classic sensorymotor

IVIG (30 g), Plasma exchange

39

Oguz-Akarsu, et al [41]

F/53

Mild fever; bilateral pneumonia

PCR+

0

Dysarthria, areflexia in LL, paraparesis

NA

Normal PCR -

Demyelinating neuropathy (AIDP)

Classic sensorymotor

Plasma exchange

40

Kilinc et al [42]

M/50

Dry cough

PCR+ IgG+

28 days

Bilateral PFP, proximal weakness 4L, areflexia, hypoesthesia LL

Neg

Normal PCR -

Demyelinating neuropathy (AIDP)

Classic sensorymotor

IVIG

41

Webb, et al [43]

M/57

Cough, headache, myalgia, malaise

PCR+

7 days

Tetraparesis, areflexia, distal hypoesthesia LL
Respiratory failure (MV)

Neg

Normal PCR -

Demyelinating neuropathy (AIDP)

Classic sensorymotor

IVIG

42

Lascano et al [44]

F/52

Dry cough, fever, odynophagia, arthralgia, diarrhoea

PCR+

15 days

Tetraplegia, areflexia, dysautonomia
Respiratory failure (MV)

Neg

ACD, PCR -

Demyelinating neuropathy (AIDP)

Classic sensorymotor

IVIG

43

Lascano et al [44]

F/63

Dry cough, odynophagia, dyspnea

PCR+

7 days

Tetraparesis, areflexia, distal paresthesia

Neg

Normal

Demyelinating neuropathy (AIDP)

Classic sensorymotor

IVIG

44

Lascano et al [44]

F/61

Productive cough, fever, myalgia, syncope, diarrhoea, nausea, vomiting

PCR+

22 days

Bilateral PFP, dysphagia, paraparesis, areflexia, dysautonomia

Neg

ACD, PCR -

Demyelinating neuropathy (AIDP)

Classic sensorymotor

IVIG

45

Guijarro-Castro et al [45]

M/70

Bilateral pneumonia

PCR+

21 days

Tetraparesis, areflexia, distal hypoesthesia LL

Neg

ACD

Demyelinating neuropathy (AIDP)

Classic sensorymotor

IVIG

46

Alberti et al [46]

M/71

Fever

PCR+

7 days

Severe flaccid tetraparesis, areflexia, distal hypoesthesia 4L

Respiratory failure (NIV, died in 24 hs)

NA

ACD, PCR -

Demyelinating neuropathy (AIDP)

Classic sensorymotor

IVIG

47

Farzi et al [47]

M/41

Cough, dyspnea, fever

PCR+

10 days

Tetraparesis, areflexia, hypoesthesia 4L

NA

NA

Demyelinating neuropathy (AIDP)

Classic sensorymotor

IVIG

48

Toscano et al [34]

M/55

Fever, cough

PCR+

10 days

Bilateral PFP, tetraplegia, areflexia, paresthesias
Respiratory failure (MV)

Neg

ACD, PCR-

Axonal neuropathy (AMAN)

Pure motor

IVIG 2 cycles

4L = 4 limbs; ACD = albuminocytological dissociation; AIDP = acute inflammatory demyelinating polyneuropathy; AMAN = acute motor axonal neuropathy; AMSAN = acute motor sensory axonal neuropathy; CVs = conduction velocities; CSF = cerebrospinal fluid; EMG = electromyography; F = female; GBS = Guillain Barré syndrome; IVIG = intravenous immunoglobulin; LL = lower limbs; M = male; MV = mechanic ventilation; NA = not available; NIV = non-invasive ventilation; Neg = negative; NR = non-reactive; OCB = oligoclonal bands; PCR = polymerase chain reaction; PFP = peripheral facial paralysis; Pt = patient; UL = upper limbs.

 

COVID-19 symptoms preceded GBS in 46 patients, including cough (60.4%), fever (56.3%), hyposmia/dysgeusia (27.1%), diarrhea (25%), asthenia/myalgia (18.8%), dyspnea (12.5%), headache (10.4%), odynophagia (10.4%), unspecified respiratory symptoms (10.4%). There were two (4.2%) patients with confirmed COVID-19 disease but no systemic symptoms (asymptomatic forms).

Six patients (12.5%) developed GBS in the absence of the most classical manifestations of COVID-19 infection. Rather than presenting respiratory symptoms, they were either asymptomatic or only manifested mild fever, diarrhea, headache, asthenia or myalgia. Therefore, it is possible that GBS may occur in unsuspected and undetected COVID-19 infected patients. COVID-19 should be assessed in every patient with GBS and its variants in the context of the current pandemic. Gigli et al reported eight patients with GBS which resulted in a 5.41-fold increment of GBS patients in 2020, compared with the period 2017-2019. They hypothesized that asymptomatic or mildly symptomatic infections may not develop an antibody response strong enough to be detected. We included in this review the only patient in this group who tested positive for COVID-19 [10].

Mean latency between the onset of COVID-19 symptoms and the first neurologic manifestations was 12.1 days (range 0-28 days). In nine patients (18.8%), GBS developed within seven days of COVID-19 infection. The remaining 37 patients developed GBS between seven and 28 days after the onset of COVID-19 symptoms. Some of these patients were diagnosed with GBS before their mild COVID-19 symptoms were recognized.

COVID-19 infection was confirmed by nasopharyngeal swab RT-PCR SARS-CoV-2 in 42 patients. The remaining six patients had negative PCR and positive IgM/IgG antibodies.

CSF testing was performed in 40 patients: 31 of them had albumin cytologic dissociation, seven were normal and two had oligoclonal bands (OCBs). Eighteen CSFs were tested for COVID-19, and only one of them showed positive IgG. Mild pleocytosis, like in our patient, may be present in GBS [7].

MRI enhancement in leptomeninges, postganglionic roots or cranial nerves, were identified in nine patients. Antiganglioside testing was performed in 25 patients: two patients with Miller Fisher syndrome (MFS) tested positive, one for anti-GD1b and a second had an equivocal anti-GM1.

Overall, 11 (22.9%) patients presented with cranial nerve involvement in the absence of muscle weakness. Three patients (6.3%; 2 males, mean age 63.6 years) presented with bilateral peripheral facial palsy (PFP) and distal paresthesias. The frequency of this variant among patients with COVID-19 seems similar than previously reported (<5%) [5]. Facial palsy was simultaneous in two patients, and sequential in our patient. All three had a good outcome. Six (12.5%) patients presented MFS (4 males, mean age 50 years); one patient had an overlapping MFS-GBS [16] and another one was defined by the author as a Miller Fisher like syndrome [19], since he did not present ophthalmoplegia. Two patients (4.2%) developed involvement of multiple cranial nerves and reduced reflexes and were defined as cranial polyneuritis. One patient presented with bilateral ptosis, dysphagia and dysphonia with hyporeflexia. The other patient had bilateral PFP, dysphagia and areflexia. This is a rare variant, previously reported [48], but not included in recent reviews [5-7]. The electrodiagnostic results were available in six patients: two patients with cranial polyneuritis presented demyelinating findings; the four remaining subjects had equivocal findings (Table I).

The classic sensory motor variant accounted for the majority of patients (n = 36, 75%, mean age 57.9 years) and only one patient presented with a pure motor variant (2.1%). The electrodiagnostic results were available in 34 patients: based on the authors report, 28 (82.4%) were classified as Acute Inflammatory Demyelinating Polyneuropathy (AIDP), six (17.6%) had an axonal neuropathy (five with Acute Motor Sensory Axonal Neuropathy [AMSAN] and one with Acute Motor Axonal Neuropathy [AMAN]). Percentages of demyelinating and axonal patterns may vary depending the set of criteria used for the definition, but AIDP predominated in the generalized forms [49-51].

Forty-two patients (87.5%) were treated initially with IVIG 2 g/kg; two received a second course of IVIG and two started plasma exchange sequentially. Two patients underwent plasma exchange initially (Table I). Four patients were not treated. There is a potential increased thrombotic risk using IVIG in patients with COVID-19 infection. This virus induces an enhanced inflammatory response leading to endothelial cell activation and a prothrombotic state [52,53]. Moreover, antiphospholipid antibodies as well as high D-dimer and increased fibrinogen levels occur in COVID-19, associated with both arterial and venous thrombotic events [54]. Nevertheless, these complications were not reported in the GBS patients treated with IVIG.

Short-term neurological outcome was favorable in 31 patients (64.6%), with a good neurologic recovery. Fourteen patients (29.2%) had respiratory failure, 11 of them needed mechanical ventilation (MV), one required non-invasive ventilation (NIV) and two (4.2%) patients died shortly after being admitted. Respiratory insufficiency in these patients is most likely the combined effect of muscle weakness due to GBS and lung infection due to COVID-19. No data was available from three patients.

It is still unclear the main pathophysiology mechanism mediating COVID-19 nerve damage. Coronavirus may invade the neuroephitelium of the olfactory nerve. Hyposmia and dysgeusia affect up to 50-85% of patients with SARS-COV-2 infection, and also may travel via retrograde axonal transport from trigeminal and vagal endings [55-57].

We therefore compared the 13 patients who developed hyposmia, hypogeusia or both with the 35 patients without these symptoms. The first group more frequently presented: a latency between the COVID-19 infection and GBS shorter than seven days (30% vs 15.6%), cranial nerve involvement in the absence of weakness (30.8% vs 17.1%) and overall cranial nerve involvement in addition to hyposmia and ageusia (76.9% vs 51%). On the other hand, the second group presented more frequently respiratory failure (31.4% vs 23.1%) and death (5.7% vs 0%) than the first group. However, none of these differences were statistically significant (Table II).

 

Table II. Clinical characteristics of patients with or without hyposmia/dysgeusia.

 

Hyposmia/Dysgeusia (+)

Hyposmia /Dysgeusia (–)

p *


Patients, n (%)

13 (27.1)

35 (72.9)

 

Age, mean (range)

59.6 (39-77)

55.6 (14-76)

NS


Latency COVID to neurologic symptoms, mean days (range)

10.6 (3-21)

12.7 (0-28)

NS


Latency <7 days, n (%)

4 (30.8)

5 (15.6)

NS


CNI without weakness, n (%)

5 (38.5)

6 (17.1)

NS


CNI, n (%)

10 (76.9)

18 (51.4)

NS


RF, n (%)

3 (23.1)

11 (31.4)

NS


Death, n (%)

0 (0)

2 (5.7)

NS


CNI = cranial nerve involvement; NS = non significant; RF = respiratory failure. *Mann Whitney U test

 

An autoimmune post infectious mechanism is the classical pathophysiology of the neural damage seen in GBS. Favors this mechanism in COVID-19 the absence of the virus in the CSF from the majority of reported GBS patients and the apparent beneficial response to IVIG. Molecular mimicry requires a shared immunologic epitope between the virus and the host. It was recently postulated that similarities between the COVID-19 spike protein, which anchors the virus to membrane gangliosides and peripheral nerve glycolipids leads to autoimmune neuropathy. Nevertheless, only one patient with MFS presented GD1A anti ganglioside antibody. Sequence analysis of 41 human proteins associated with immune-mediated polyneuropathies identified shared hexapeptides between the SARS-CoV-2 virus and the human heat shock proteins 60 and 90 [58]. Viral peptides could also trigger autoimmunity through direct activation of autoreactive T cells against host antigens or indirectly through activation of antigen presenting cells that stimulate preprimed autoreactive T cells in a process known as bystander activation [59].
 

Conclusions


Limitations of this review include the small number of reported patients and the variable information regarding their clinical and diagnostic studies. Prevalence of GBS associated with COVID-19 is still unknown and it is possible that not only mild GBS patients like ours may not be diagnosed as a GBS variant, but also severely affected patients may be confused with critical illness polyneuropathy. Nevertheless, GBS in patients with SARS-CoV-2 infection resembles clinically and electrophysiology the classical forms. Further studies are necessary to understand whether GBS frequency is actually increased due to SARS-CoV-2 infection and explore pathogenic mechanisms. Neurologists should consider testing all patients with GBS for COVID-19 infection because they may be asymptomatic or lack the classical respiratory symptoms.

 

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Síndrome de Guillain-Barré asociado a infección por COVID-19: revisión de casos publicados

Introducción. La pandemia por la enfermedad por coronavirus 2019 (COVID-19) es un importante problema para la salud mundial. Hay un incremento en las complicaciones neurológicas reconocidas por la COVID-19, incluyendo el síndrome de Guillain-Barré (SGB) y sus variantes.

Desarrollo. Se realizó una revisión de los casos publicados en los últimos meses de SGB asociado a infección por COVID-19. Incluimos a 48 pacientes (31 hombres; edad media: 56,4 años). Los síntomas de COVID-19 más comunes fueron tos (60,4%) y fiebre (56,3%). El tiempo promedio entre los síntomas de COVID-19 y el SGB fue de 12,1 días, pero nueve pacientes (18,8%) desarrollaron SGB en menos de siete días. Once pacientes (22,9%) presentaron afectación de los nervios craneales en ausencia de debilidad muscular, 36 presentaron la variante clásica sensitivomotora (75%) y uno tuvo una variante motora pura (2,1%). El patrón electrofisiológico se consideró desmielinizante en el 82,4% de las variantes generalizadas. La presencia de hiposmia/disgeusia estuvo asociada con una latencia menor a los siete días hasta el inicio de los síntomas del SGB (30 frente a 15,6%) y a la afectación de los nervios craneales en ausencia de debilidad (30,8 frente a 17,1%). La mayoría de los pacientes (87,5%) fueron tratados con inmunoglobulina endovenosa. La evolución neurológica fue favorable en el 64,6%, el 29,2% tuvo insuficiencia respiratoria y hubo un 4,2% de muertes.

Conclusiones. El SGB en pacientes con infección por SARS-CoV-2 es similar clínica y electrofisiológicamente a las formas clásicas. Se requieren más estudios para comprender si la frecuencia del SGB realmente aumentó debido a la pandemia por COVID-19 y explorar los mecanismos patógenos involucrados.

Palabras clave. COVID-19. neuropatía motora axonal aguda. neuropatía sensitivomotora axonal aguda. parálisis facial bilateral. polineuropatía desmielinizante inflamatoria aguda. SARS-CoV-2. síndrome de Guillain-Barré. síndrome de Miller Fisher.

 

© 2021 Revista de Neurología

 

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